CN107207696B

CN107207696B - Biodegradable polymers

Info

Publication number: CN107207696B
Application number: CN201580075333.3A
Authority: CN
Inventors: D·科恩
Original assignee: Yissum Research Development Co of Hebrew University of Jerusalem
Current assignee: Yissum Research Development Co of Hebrew University of Jerusalem
Priority date: 2015-01-02
Filing date: 2015-12-31
Publication date: 2023-05-23
Anticipated expiration: 2035-12-31
Also published as: WO2016108242A1; CN107207696A; IL252833A0; EP3240819A1; IL252833B; BR112017014351A2; US20170369628A1

Abstract

The present invention provides a class of polymeric materials which are ABA-triblock or AB-diblock, comprising biodegradable segments and poly (propylene oxide) (PPO) segments, and uses thereof.

Description

Biodegradable polymers

Technical Field

The present invention relates generally to a novel class of polymers and their use, for example in the construction of medical devices such as sutures.

Background

Up to 20% of patients undergoing abdominal wall opening (Laparotomy) surgery (abdominal wall opening surgery) will develop a condition known as postoperative abdominal hernia (Post Operative Ventral Hernia) (POVH) within 5 years. POVH means that when the intestine can become narrowed, this tissue is broken through by the intestine, which is usually contained in the abdominal wall, which results in pain, disfigurement and even death in the afflicting person.

The normal healing of the abdominal wall is such that within two months of closure, the abdominal wall regains 80% of its original strength. Gold standard surgical sutures provide tissue support for up to two months. Three main factors lead to the appearance of POVH: (1) physician error, (2) patient physiology, and (3) improper use of occlusive material. The most important factor for POVH appears to be the physiology of the patient. Studies have shown that the chance of effective wound healing is greatly reduced in immunosuppressed patients, the elderly, patients undergoing chemotherapy, patients under steroid therapy, and a wide variety of other patients.

The way to overcome this risk factor and reduce the occurrence of POVH is by increasing the support to the tissue, allowing the tissue to heal in more time. One such support is typically provided by sutures, which are traditionally used in surgery, for example, to close a wound, for holding tissue together during various surgical procedures (surgical procedure). Each absorbable suture has an absorption profile that specifies the time it takes for the suture to fully degrade and be expelled from the body. A medical consensus for sutures is that they remain in the tissue for the smallest possible period of time after achieving their intended purpose. The intended purpose of an absorbable suture is measured by the ability of the suture to maintain sufficient tensile strength until the intended tissue is self-sufficient.

As mentioned, 80% of patients receiving surgery are immunocompromised, meaning that typical sutures that provide 2 months of support will not provide sufficient tensile strength to allow the abdominal wall to heal and reach a self-supporting stage. Studies have shown that immunocompromised patients require prolonged support of the abdominal wall in the range of 3-5 months to allow adequate healing of the abdominal wall. Such sutures, which are also characterized by a rapid rate of absorption (absorption rate), will help minimize POVH associated with inadequate tissue support in immunocompromised patients.

Summary of The Invention

Accordingly, in order to provide a superior class of sutures and other medical devices that do not have the drawbacks associated with currently available equivalents, the inventors of the technology disclosed herein have developed a novel and unique class of biodegradable polymers that can be manipulated in composition, structure, and form to suit a wide variety of medical and other purposes.

As is known in the art, the rate of polymer degradation, which depends on many parameters, will increase as a function of the hydrophilicity of the polymer. In other words, one would expect to observe increased degradation in the more hydrophilic polymers. This is generally due to the fact that: more hydrophilic polymers attract more (or more rapidly) water molecules that hydrolyze groups that are responsible for degradation; such groups may be aliphatic ester groups present along the polymer backbone (polymeric backbone), which lead to chain cleavage and concomitant reduction in polymer molecular weight.

An additional key factor is the crystallinity of the polymer. Since the crystalline phase consisting of a close array of polymer chains is denser and dense when compared to the amorphous, more open equivalent, diffusion of water molecules into the crystalline phase is significantly hindered. Thus, the higher the crystallinity of the biodegradable polymer, the slower its degradation.

All other parameters being equal, a polymer comprising hydrophilic polyethylene oxide (PEO) segments is expected to degrade faster than its counterpart comprising hydrophobic polypropylene oxide (PPO) segments.

The inventors of the present invention have developed a unique class of tri-block and di-block hydrophobic polymers that degrade and behave like their hydrophilic counterparts, contrary to the well known facts described above. This "switched" or "reversed" behavior that is not expected in the novel class of polymers of the present invention is believed to result from the unique arrangement of polymer fragments, as otherwise disclosed herein.

The polymers of the invention have tri-block or di-block structures of various molecular weights with a central PPO segment and two (tri-block) or one (di-block) outboard bioabsorbable segments (bioabsorbable segment) such as Polycaprolactone (PCL) segments that are chain extended (tri-block) or coupled (di-block) using various difunctional reactive molecules. When the polymers of the invention comprise PCL fragments, these polymers are denoted PPCA. Surprisingly, it was found that PPCA polymers degrade at the same rate as their polyethylene oxide containing counterparts (PECA). This applies to a range of ethylene oxide/caprolactone (EO/CL) and propylene oxide/caprolactone (PO/CL) ratios.

The polymers of the invention, as exemplified for PPCA polymers, are described according to the following nomenclature: the name of the polymer PPCA will be followed by the molecular weight of the PPO fragment, which is divided by the ratio between the number of PPO repeat units present in the PPO fragment divided by the number of CL units present in the triblock (both outer fragments) or di-block.

Thus, for example, PPCA 2,000/0.1 represents a PPCA polymer having a molecular weight of 2,000da and characterized by a ratio of the number of PPO repeat units (present in the PPO fragment) divided by 0.1 between the number of CL units (constructed from a central PPO fragment and two PCL fragments optionally chain extended, crosslinked or coupled using various functionality reactive molecules).

Both PECA 2,000/0.1, which is a comparative polymer used in analyzing PPCA 2,000/0.1, and the polymer PPCA 2,000/0.1 according to the present invention degrade at similar rates, even though PECA 2,000/0.1 absorbs three times the water compared to PPCA 2,000/0.1. This observation is notable, not only in view of the fact that the more hydrophobic polymer exhibits substantially the same degradation rate as the less hydrophobic polymer or the more hydrophilic polymer, but also in view of the fact that the PECA polymer has a higher crystallinity (more crystalline) than its PPCA counterpart. This is demonstrated by the fact that: the PECA polymer has a crystallinity of 26% and exhibits a melting point at 54 ℃, whereas its PPCA counterpart, the polymer according to the invention, has a crystallinity of 38% and exhibits a melting point at 58 ℃. This surprising observation means that the PCL fragment present in PPCA is 46% more crystalline than the PCL fragment of the same length present in PECA.

The presence of PEO fragments with their own crystallinity reduces the ability of PCL to crystallize, while amorphous, highly flexible PPO fragments allow for better crystallization of PCL. In the case of PECA, the central segment blocks the ability of PCL to crystallize, while in the case of PPCA, the central segment enhances mobility and crystallinity.

In addition, at time zero, meaning that the polymer of the present invention has been found to be 13% stronger than its PECA counterpart when dried. PECA polymers exhibit increased stiffness (greater than 50% increase in young's modulus after 120 days), which can lead to unraveling of the suture knot when used as a suture for medical purposes. The polymers of the present invention have been found to be suitably flexible during suturing and are more suitable for wound closure and other clinical indications.

Thus, in a first aspect, there is provided a polymeric material selected from ABA tri-blocks and AB di-blocks, wherein a is a biodegradable segment and B is a poly (propylene oxide) (PPO) segment.

Biodegradable polymeric materials comprising PPO fragments and biodegradable components are also contemplated. Biodegradable polymeric materials comprising PPO segments and biodegradable aliphatic polyester components are also provided.

Biodegradable polymeric materials are also contemplated, comprising PPO fragments and one or more aliphatic polyester components, each of which is chain extended and/or coupled and/or crosslinked.

In certain embodiments, the polymeric materials of the present invention may be generally described as selected from ABA tri-blocks and AB di-blocks, where a is a biodegradable segment and B is a poly (propylene oxide) (PPO) segment, where the polymeric material is optionally chain extended, coupled or crosslinked using a chain extender (or linkage), a coupling segment (or linkage), or a crosslinking segment (or linkage), respectively.

The term "polymer" is used to describe materials known in the art having an average molecular weight of from about 1,000-3,000 to millions, for example 5 million or more daltons (Da), including relatively low molecular weight oligomers.

In some embodiments of the present invention, in some embodiments, molecular weights between 1,000 and 100,000Da, between 1,000 and 90,000Da, between 1,000 and 80,000Da, between 1,000 and 70,000Da, between 1,000 and 60,000Da, between 1,000 and 50,000Da, between 1,000 and 40,000Da, between 1,000 and 30,000Da, between 1,000 and 20,000Da, between 1,000 and 10,000Da, between 1,000 and 9,000Da, between 1,000 and 8,000Da, between 1,000 and 7,000Da, between 1,000 and 6,000Da, between 1,000 and 5,000Da, between 1,000 and 4,000Da between 1,000 and 200,000da, between 1,000 and 300,000da, between 1,000 and 400,000da, between 1,000 and 500,000da, between 1,000 and 600,000da, between 1,000 and 700,000da, between 1,000 and 800,000da, between 1,000 and 900,000da, between 1,000 and 1,000,000da, between 1,000 and 2,000,000da, between 1,000 and 3,000,000da, between 1,000 and 4,000,000da, between 1,000 and 1,500,000da, between 1,000 and 2,500,000da, between 1,000 and 3,500,000da or between 1,000 and 4,500,000 da.

The polymers of the present invention are "tri-blocks" or "di-blocks".

The tri-block polymers of the present invention have a general structure ABA comprising a first polymer that is an a block, in certain embodiments an a block is a polyester segment covalently linked to a poly (propylene) that is a B block, covalently linked to a second polymer segment that is a second a block that may independently also be a polyester segment, as depicted in the general tri-block of formula ABA. The two a blocks need not be identical.

The tri-blocks according to the present invention may be terminated with one or more hydroxyl moieties, amine moieties or carboxyl moieties or a combination thereof to enable them to be further extended or combined with other materials. In certain embodiments, the polymer may be terminated with hydroxyl groups that can be readily covalently linked to chain extenders, crosslinkers, or other groups optionally comprising electrophilic moieties, thereby enabling the ready production of a variety of polymers according to the invention.

The term di-block polymer has the general structure AB, comprising a first polymer a block, in certain embodiments, the a block is a polyester segment, such as a poly (hydroxycarboxylic acid) polyester, covalently linked to a poly (propylene) that is a B block, as described above.

The terms "segment" and "block" will be used interchangeably in this document. Each segment or block may be the same or different. For example, each of biodegradable segments a may be the same or different.

"Poly (hydroxycarboxylic acid)" is a unit derived from an aliphatic hydroxycarboxylic acid or related ester or dimer ester (dimer ester), including cyclic di-polyesters such as, for example, lactic acid, lactide, glycolic acid, glycolide, or related aliphatic hydroxycarboxylic acids or lactones such as, for example, epsilon-caprolactone, delta-glutarate lactone, delta-valerolactone, gamma-butyrolactone, and mixtures thereof, as well as many others as set forth herein.

The term "biodegradable" generally refers to the ability of the polymers of the invention to degrade in vivo. When stated in relation to fragment a, the term refers to the ability of the molecular fragment defining the a block to biodegrade in vivo and cause degradation of the polymer as a whole.

The polymers according to the invention degrade and decompose in vivo into monomer units such as hydroxy acids. Degradation of the polymers of the invention occurs primarily by hydrolysis of reactive bonds in the a blocks, such as aliphatic esters. The hydrolysis reaction is generally dependent on pH. The rate constants of hydrolysis tend to be much greater at higher pH (greater than 9.0) and lower pH (less than 3.0) than at neutral pH (6.0 to 8.0).

In the case of the hydrophilic, in some cases water-soluble chain extenders and cross-linkers which can be used in gels and viscous solutions according to the invention, these chain extenders and cross-linkers, which are generally highly hydrophilic and in some cases highly water-soluble, tend to be non-biodegradable. Furthermore, when using a polymer comprising an a block derived from a hydroxy acid, the polymer a block will degrade into individual hydroxy acids which are useful in biosynthesis and may be involved in the "biochemistry" of the patient.

In the present inventionThe di-block may be formed, for example, by initiating polymerization of a hydroxycarboxylic acid (or equivalent monomer, dimerization or related building block) with a hydroxy-, amine-or carboxy-terminated poly (propylene) block terminated by a non-reactive group (on one end of the polymer). The non-reactive groups may be selected, for example, from alkyl, aryl or aralkyl groups or substituted alkyl, aryl or aralkyl groups, e.g. C ₁ -C ₁₂ An alkyl group or equivalent may be removed to provide a protecting group for the free nucleophilic moiety at a later stage. The resulting di-blocks may then be further reacted with chain extenders, crosslinkers and the like to produce polymers according to the invention having a desired or advantageous PO/CL ratio. The di-blocks can be used in almost the same way as ABA tri-blocks are used in the present invention, i.e. as building polymer units for the polymers according to the present invention.

The material names "poly (propylene glycol)", "poly (oxypropylene) (poly (oxypropylene))" and "poly (propylene oxide)" all abbreviated to PPO are used interchangeably herein in describing the materials of the present invention or in accordance with the present invention. These polymers having varying molecular weights are used for the B blocks of ABA tri-blocks and AB di-blocks and the chain extenders and crosslinkers according to the invention.

The phrases "poly (alkylene oxide) -containing" and "poly (propylene oxide) -containing" are used to describe certain polymer chains or segments that contain at least a certain amount or number (1 or more) of poly (alkylene oxide) or poly (propylene oxide) units.

The phrases "poly (alkylene oxide) -rich" and "poly (propylene oxide) -rich" are used to describe certain polymeric materials that comprise at least 40% by weight of poly (alkylene oxide) or poly (propylene oxide) of the total weight of the polymeric material.

The polymers of the present invention are ABA tri-blocks or AB di-blocks, where a is a biodegradable component, in some cases a polyester, in some embodiments an oligomer or polymer comprising degradable units, optionally derived from hydroxy acid units or lactones and the like thereof, and B is based on PPO.

As known in the art, a "polyester" is a unit derived from an aliphatic hydroxycarboxylic acid or related ester, lactone, diester, carbonate, anhydride, dioxanone (dioxanone) or related monomer, such unit may be derived from: lactic acid, lactide, glycolic acid, glycolide or related aliphatic hydroxycarboxylic acids, esters (lactones), dimer acids, carbonates, anhydrides, orthoesters, and dioxanones; or related compounds such as, for example, β -propiolactone, epsilon-caprolactone, delta-glutaryl lactone, delta-valerolactone, β -butyrolactone, pivalolactone, α, α -diethylpropiolactone, ethylene carbonate, trimethylene carbonate (trimethylene carbonate), γ -butyrolactone, p-dioxanone, 1, 4-dioxacycloheptan-2-one, 3-methyl-1, 4-dioxane-2, 5-dione, 3-dimethyl-1, 4-dioxane-2, 5-dione, α -hydroxybutyric acid, α -hydroxyvaleric acid, α -hydroxyisovaleric acid, α -hydroxycaproic acid, α -hydroxy- α -ethylbutyric acid, α -hydroxyisohexanoic acid, α -methyl valeric acid, α -hydroxyheptanoic acid, α -hydroxystearic acid, α -hydroxyditetradecanoic acid, cyclic esters of salicylic acid, and mixtures thereof.

In certain embodiments, hydroxy acids (e.g., alpha-hydroxy acids) and their corresponding cyclic di-polyesters, such as caprolactone, lactide, and glycolide, are used according to the present invention.

In certain embodiments, the a-block material comprises hydroxy acid units derived from an aliphatic hydroxy carboxylic acid or related acid, ester, or similar compound.

In certain embodiments, the a block material is selected from lactic acid, lactide, glycolic acid, glycolide, and related aliphatic hydroxycarboxylic acids or aliphatic hydroxycarboxylic acid esters (lactones), and combinations thereof.

In certain embodiments, the a block material is selected from the group consisting of β -propiolactone, epsilon-caprolactone, delta-glutaryl lactone, delta-valerolactone, β -butyrolactone, pivalolactone, α, α -diethylpropiolactone, ethylene carbonate, trimethylene carbonate, γ -butyrolactone, p-dioxanone, 1, 4-dioxacyclohepta-2-one, 3-methyl-1, 4-dioxane-2, 5-dione, 3-dimethyl-1, 4-dioxane-2, 5-dione, α -hydroxybutyric acid, α -hydroxyvaleric acid, α -hydroxyisovaleric acid, α -hydroxycaproic acid, α -hydroxy- α -ethylbutyric acid, α -hydroxyisohexanoic acid, α -hydroxy- α -methylpentanoic acid, α -hydroxyheptanoic acid, α -hydroxystearic acid, α -hydroxytetracosanoic acid, cyclic esters of salicylic acid, and mixtures thereof.

In certain embodiments, the a-block material comprises poly (hydroxy-carboxylic acid), such as poly (glycolic acid), poly (L-lactic acid), and poly (D, L-lactic acid) and polycaprolactone, and combinations thereof.

In certain embodiments, the B blocks in the tri-and di-blocks of the present invention are selected from hydroxyl, carboxylic acid or amine terminated poly (propylene oxide) blocks (hydroxyl terminated in certain embodiments) covering a wide range of molecular weights. In certain embodiments, the poly (propylene oxide) block is not linear and may be branched; or any other spatial configuration having more than two functionalities (i.e., the number of reactive end groups).

In certain embodiments, not all poly (propylene oxide) end groups react with the biodegradable chain a, which is typically an aliphatic polyester segment, but remain unreacted or react with other components.

The tri-block or di-block is optionally hydroxy terminated and chain extended using a difunctional chain extender such as a diisocyanate, dicarboxylic acid ester, diester or diacyl halide (diacyl) group to chain extend the tri-block to produce higher molecular weight polymer chains. Alternatively, the tri-blocks may be terminated with groups such as the following to produce chain extended or coupled polymers having higher molecular weights: carboxylic acids or carboxylic acid ester moieties (which may be reacted directly as ester groups, activated as "active" ester groups or converted to active acyl groups such as acyl halides) or isocyanate groups or other groups capable of reacting with the terminal groups of difunctional chain extenders or coupling agents such as glycols, diamines or hydroxylamines or polyoxyethylene (polyethylene glycols) or poly (ethylene oxide) -co-poly (propylene oxide) block copolymer chain extenders (particularly in the case of water soluble or water dispersible gels, dispersions or viscous solutions), and many others.

The polymer according to the invention optionally comprises a chain-extended tri-block or coupled di-block having a relatively high molecular weight, covering a range of molecular weights, providing polymer properties according to the invention that are advantageously used for fibers. In certain embodiments, the tri-block and di-block are reacted with molecules having a functionality greater than two.

In certain aspects of the invention, the polymers used in the present invention have the following characteristics: they are prepolymerized, chain extended or coupled, substantially uncrosslinked and biodegradable. In other cases, the polymer may be crosslinked. The polymers of the present invention are advantageously used as fibers, sutures and staples (staples). The polymers used in fibrous structures such as sutures according to the present invention are sufficiently strong and flexible to enable the suture to perform satisfactorily over the required period of time, yet exhibit enhanced suture ability (subtotal) and knottability (knowability).

In certain aspects of the invention, the polymers disclosed herein combine tri-blocks and di-blocks. In certain aspects of the invention, the polymers disclosed herein are chain extended and/or coupled and/or crosslinked, with each of these three alternative pathways being performed simultaneously or sequentially.

In certain embodiments, the tri-block or di-block is first chain extended or coupled and then crosslinked.

In other embodiments, the tri-block or di-block is first chain extended or coupled, then stretched, and the molecule is oriented longitudinally, and then crosslinked.

As used below, the polymers of the present invention are members of the PPCA family, each member comprising poly (propylene oxide) and poly (caprolactone) blocks, optionally chain extended, for example with a diisocyanate, such as hexamethylene diisocyanate. The PPCA polymers of the invention are generally specified in terms of their composition by the average molecular weight of the poly (propylene oxide) chains and by their PO/CL ratio, where PO is the number of propylene oxide units present and CL is the total number of caprolactone (caprolacton) units (ester units) present. A general definition of the PO/CL ratio is provided below.

In certain embodiments of the present invention, ABA tri-blocks are substantially water insoluble units comprising biodegradable blocks, such as poly (hydroxy acid) blocks and poly (propylene oxide) blocks. The a blocks of the ABA tri-blocks of the polymers of the present invention are biodegradable and range in size from one monomer unit (the monomer units within the a block are considered caprolactone, lactic acid, glycolic acid or related hydroxy acid (ester) units, even where caprolactone and/or lactide and/or glycolide or related reactants comprising more than one hydroxy acid unit are used to produce the a block) up to thousands of units, such as about 600 or more monomer units, with the size in the range from about 4 to about 400 units or from about 10 to about 200 units, depending on the length or molecular weight of the poly (propylene oxide) fragment combined with the a block in the tri-block. It should be noted that the size of the A block can fall well outside the above range, depending on the overall physical properties of the ABA tri-block formed and the size of the B block

In certain embodiments, the a block is derived from a hydroxy acid as described above, or from units of glycolic acid, lactic acid (L or D, L mixtures to promote biodegradability), caprolactone, or mixtures thereof in the form of glycolide, lactide, or caprolactone reactants (as explained further below). In certain embodiments, in the polymers to be used in making fibers and sutures, the a blocks tend to create hard domains (hard domains) in the matrix and generally provide strength and structural integrity to the polymer. The a blocks are water insoluble and are optionally sized in combination with poly (propylene oxide) fragments in order to promote phase separation between the a blocks and B blocks in ABA tri-blocks or AB di-blocks and to promote the final polymer to be used as a suture and for his clinical application. Thus, the a block infuses the final polymer with the necessary structural properties, which in combination with the B block results in a polymer with excellent mechanical properties and controlled biodegradability. Furthermore, in certain embodiments according to the present invention, the length of the a block is believed to be important for providing materials with phase separated microstructures.

The size of the poly (propylene oxide) B block can vary from about 100Da (daltons units) up to about 200,000Da or more, or in the range of about 400Da up to about 20,000 Da. In certain embodiments, the size of the poly (propylene oxide) block is in the range from about 400Da to about 10,000 Da. Based on the teachings of the present invention, one of ordinary skill will know to vary the length of the B and a blocks to provide polymers with superior properties, which makes them particularly suitable for performing as wound closure devices such as sutures and staples, depending on the type of final formulation desired and the manufacturing process they are subjected to.

ABA tri-blocks or AB di-blocks according to the invention are generally described in terms of their PO/CL ratio. This ratio is the number of monomer repeat units of the poly (propylene oxide) B block (repeat units are propylene oxide units) divided by the total number of monomer units in the a block. The polymers comprising ABA tri-blocks or AB di-blocks which are chain extended, coupled or crosslinked according to the invention can also be described in terms of the PO/CL ratio of the polymer, in which case the PO/CL ratio represents only the ratio of propylene oxide units to hydroxy acid monomer units in the total polymer.

The PO/CL ratio of the total polymer can be determined by NMR analysis. These polymers can also be specified with respect to their composition by the average molecular weight of the poly (propylene oxide) (PPO) chains (chain) or chains (chain) and by the weight percentage of the PPO chains (chain) or chains (chain) in the tri-block, di-block or total polymer. However, it should be noted that in the case where the chain extender, coupling agent or crosslinking agent comprises poly (propylene oxide) chains, the PO/CL ratio of the polymer may be quite different from the PO/CL ratio found in ABA tri-blocks or AB di-blocks (the total amount of PO may become significantly greater due to the contribution of PO from the chain extender and thus the PO/CL ratio of the polymer may be significantly greater than the PO/CL ratio of ABA tri-blocks or AB di-blocks). Likewise, the weight percent of PPO found in such polymers may also be very different from the weight percent found in ABA tri-blocks or AB di-blocks.

Without being limited by the statements, the concept of PO/CL ratio can be exemplified by a polymer described as poly (propylene oxide)/polycaprolactone block copolymer (PPCA) 2,000/0.5, which is an ABA tri-block comprising PPO chains with an average molecular weight of 2,000Da and hexamethylene diisocyanate chain extension at a PO/CL ratio of 0.5. Thus, the tri-block in this polymer comprises a 2,000 molecular weight PPO segment for a B block comprising about 35 propylene oxide units and two a blocks, each a block comprising an average of about 35 CL units. Alternatively, the same polymer may be designated 2,000/80%, where 2,000 is the average molecular weight of the PPO chain and 80% is the weight percent of PCL in the ABA tri-block. For this PPCA 2,000/0.5 polymer, the molecular weight of the tri-block is about 7,980 (2,000 for PPO chains, and two polycaprolactone a blocks, each having a molecular weight of about 3,990, totaling 7,980 for the two a blocks). Thus, the weight percent of PPO blocks in this tri-block is 20% (2,000/9,980).

Alternatively, for example, the ABA tri-blocks described above may be chain extended with a wide variety of chain extenders, which differ in the following ways: its composition, molecular weight, degree of hydrophilicity, stiffness, being biodegradable or not, or exhibiting other advantageous characteristics, such as rendering the polymers of the present invention stimulus responsive. This is exemplified by HDI-PEG4000-HDI, which is formed by reacting poly (ethylene oxide) chains of molecular weight 4,000 with two moles of hexamethylene diisocyanate. After reacting this chain extender with the ABA tri-block described above, the repeat units along the backbone are:

[-(CL) ₃₅ -PPO2000-(CL) ₃₅ -HDI-PEG4000HDI-] _x ，

Wherein x represents the degree of polymerization of the repeating units; more specifically, the average number of repeating units present per molecule of polymer.

The above can also be exemplified by the use of environmentally-responsive polymers that are end-capped with groups capable of reacting with the end groups of the ABA tri-block. The polymers intended to render the present invention have a reversed thermo-responsive polymer, such as PEO-PPO-PEO triblock, can be end-capped with groups capable of reacting with the end-groups of ABA tri-block or AB di-block, which renders the polymer desirable additional capabilities.

The PO/CL ratio of the polymer according to the invention is in the range of from about 0.05 to about 100 or more, or about 0.1 to about 30, or from about 0.2 to about 10. In some cases, the PO/CL ratio may fall outside of these ranges, depending on the final properties of the polymer desired. The PO/CL ratio of the individual polymers may also vary depending on the size of the B block and the type of chain extender used. In certain embodiments, as the size (molecular weight) of the B block in the tri-block increases, the PO/CL ratio will tend to be slightly smaller than in tri-blocks and polymers where the size of the B block is smaller.

Based on the teachings of the present invention one of ordinary skill in the art will know to vary the length of the a blocks and B blocks in a manner that provides a polymer with controlled mechanical properties and biodegradability as defined by its biomedical use.

Thus, in view of the foregoing, the following embodiments provide polymers for use in medical and non-medical applications according to the present invention.

In certain embodiments, in the tri-block or di-block of the present invention, a is a polymer comprising aliphatic ester units. In certain embodiments, the aliphatic ester units are derived from hydroxy acid units, or from their related esters or lactones.

In certain embodiments, a is a polymer fragment comprising at least one of: lactic acid; lactide; glycolic acid; glycolide; an aliphatic hydroxycarboxylic acid or aliphatic hydroxycarboxylic acid ester (lactone) selected from the group consisting of beta-propiolactone, epsilon-caprolactone, delta-glutaryl-lactone, beta-butyrolactone, pivalolactone, alpha-diethylpropiolactone, ethylene carbonate, trimethylene carbonate, gamma-butyrolactone, p-dioxanone, 1, 4-dioxacyclohepta-2-one, 3-methyl-1, 4-dioxane-2, 5-dione, 3-dimethyl-1, 4-dioxane-2, 5-dione; cyclic esters of α -hydroxybutyric acid, α -hydroxyvaleric acid, α -hydroxyisovaleric acid, α -hydroxycaproic acid, α -hydroxy- α -ethylbutyric acid, α -hydroxyisohexanoic acid, α -hydroxy- α -methylpentanoic acid, α -hydroxyheptanoic acid, α -hydroxystearic acid, α -hydroxytwenty-four carboxylic acid; salicylic acid and mixtures thereof.

In certain embodiments, a comprises poly (glycolic acid), poly (L-lactic acid), poly (D, L-lactic acid), or polycaprolactone, or any combination thereof.

In certain embodiments, the B block comprises a hydroxy, carboxylic acid, or amine terminated PPO fragment.

In certain embodiments, B comprises poly (propylene oxide) and each of a comprises poly (caprolactone).

In certain embodiments, ABA tri-block or AB di-block polymers are chain extended or coupled using at least one difunctional compound capable of reacting with the end capping groups of the tri-block or di-block. In certain embodiments, the difunctional compound is a diisocyanate. In certain embodiments, the diisocyanate is Hexamethylene Diisocyanate (HDI).

In certain embodiments, the bifunctional compound comprises two molecular fragments having functionality and an intermediate fragment linking the two molecular fragments. In certain embodiments, the intermediate fragment is a polyoxyalkylene. In certain embodiments, the intermediate segment is a polyester.

In certain embodiments, the polyalkylene oxide is polyethylene oxide, polypropylene oxide, polytetrahydrofuran (polytetramethylene oxide), or any combination or copolymer thereof.

In certain embodiments, the polyester is polycaprolactone, polylactic acid, polyglycolic acid, or any combination or copolymer thereof.

In certain embodiments, the difunctional compound is selected from diisocyanates. In certain embodiments, the diisocyanate is Hexamethylene Diisocyanate (HDI).

In certain embodiments, the polymer of the present invention is selected from the group consisting of polymers of formula (I):

{-[-(O-(CH ₂ ) _j -CHR ₁ -CO) _b -(O-CHCH ₃ -CH ₂ -) _m -O-(CO-CHR ₁ -(CH ₂ ) _j -O-) _a -CO-NH-R'-NH-CO]-} _x (formula I)

Wherein the method comprises the steps of

Each a and b is independently an integer between 1 and 2,000,

m is an integer between 2 and 1,000,

each j is independently an integer between 0 and 20,

r' is selected from C ₂ -C ₂₀ Alkylene, C ₅ -C ₂₀ Cycloalkyl, C-containing ₅ -C ₂₀ Cycloalkyl groups, aryl-containing groups, polymer fragments, oligomer fragments,

each R ₁ Independently of one another, H or C ₁ -C ₁₂ Alkyl group, and wherein

x is an integer defining the number of repeating units in the polymer of the invention, x can be between 1 and 1,000.

In certain embodiments, x is between 1 and 900, between 1 and 800, between 1 and 700, between 1 and 600, between 1 and 500, between 1 and 400, between 1 and 300, between 1 and 200, between 1 and 100, between 10 and 900, between 20 and 900, between 30 and 900, between 40 and 900, between 50 and 900, between 60 and 900, between 70 and 900, between 80 and 900, between 90 and 900, between 100 and 900, between 200 and 900, between 300 and 900, between 400 and 900, or between 500 and 900.

In certain embodiments, a is between 1 and 1,400, between 1 and 1,000, between 1 and 500, between 1 and 200, between 1 and 100, between 1 and 90, between 1 and 80, between 1 and 70, between 1 and 60, between 1 and 50, between 1 and 40, between 1 and 30, between 1 and 20, or between 1 and 10.

In certain embodiments, b is between 1 and 1,400, between 1 and 1,000, between 1 and 500, between 1 and 200, between 1 and 100, between 1 and 90, between 1 and 80, between 1 and 70, between 1 and 60, between 1 and 50, between 1 and 40, between 1 and 30, between 1 and 20, or between 1 and 10.

In certain embodiments, m is between 2 and 900, between 2 and 500, between 2 and 200, between 2 and 100, between 2 and 90, between 2 and 80, between 2 and 70, between 2 and 60, between 2 and 50, between 2 and 40, between 2 and 30, between 2 and 20, or between 2 and 10.

In certain embodiments, j is 0. In certain embodiments, j is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In certain embodiments, a and b are the same. In certain embodiments, a and b are different.

In certain embodiments, all integers j are the same.

In certain embodiments, R' is an aryl group selected from naphthyl and phenyl. In other embodiments, R 'is selected from the group consisting of 4,4' -diphenylmethane, 3 '-dimethylphenyl, 3' -dimethyl-diphenylmethane, 4,6'-xylylene (4, 6' -xylylene), and p-phenylene.

In certain embodiments, R' is C ₂ -C ₁₂ Alkylene or C ₅ -C ₁₂ Cycloalkyl groups. In certain embodiments, R 'is selected from the group consisting of 4,4' -dicyclohexylmethane, isophorone, lysine, cyclohexyl, 3, 5-trimethylcyclohexyl, and 2,4-trimethylhexamethylene (2, 4-trimethylhexamethylene).

In certain embodiments, R' is a polymer fragment or an oligomer fragment. The polymer or oligomer segments are optionally selected from the group consisting of polypropylene oxide, polypropylene oxide-containing chains, polypropylene oxide-rich chains, polytetrahydrofuran-containing chains, polytetrahydrofuran-rich chains, polyethylene oxide-containing chains, polyethylene oxide-rich chains, copolymers of polyethylene oxide and polypropylene oxide, polydimethylsiloxane, polydimethylsiloxane-containing chains, polydimethylsiloxane-rich chains, polycaprolactone-containing chains and polycaprolactone-rich chains, oligopeptides-containing chains, oligopeptides-rich chains, oligosaccharides-containing chains, oligosaccharide-rich chains, oligomers or copolymers of polymers and addition polymers, and combinations thereof.

In certain embodimentsJ=0. In other embodiments, R ₁ is-CH ₃ . In further embodiments, R ₁ is-H.

In certain embodiments, R' is isophorone or lysine.

In certain embodiments, j=0 and R ₁ is-H.

In certain embodiments, j=0 and R ₁ is-CH ₃ 。

In certain embodiments, R' is a hexamethylene group (C ₆ Alkylene group), j=4 and R ₁ is-H.

In certain embodiments, the polymer of the present invention is selected from the group consisting of polymers of formula (II):

{-(O-(CH ₂ ) _j -CHR ₁ -CO) _r -(O-CHCH ₃ -CH ₂ -) _m -O-(CO-CHR ₁ -(CH ₂ ) _j -O-) _k -CO-NH-R'-NH-CO-R”'-CO-NH-R'-NH-CO-} _z (formula II)

Wherein the method comprises the steps of

Each r and k independently of the other is an integer between 1 and 2,000,

m is an integer between 2 and 1,000,

each j is independently an integer between 0 and 20,

each R' is independently selected from C ₂ -C ₂₀ Alkylene, C ₅ -C ₂₀ Cycloalkyl, C-containing ₅ -C ₂₀ Cycloalkyl groups, aryl-containing groups, polymer fragments, oligomer fragments, and

r' "is selected from the group consisting of polymeric fragments and oligomeric fragments,

each R ₁ Is H or C ₁ -C ₁₂ An alkyl group, a hydroxyl group,

z is an integer defining the number of repeating units in the polymer of the invention, and z may be between 1 and 1,000.

In certain embodiments, z is between 1 and 900, between 1 and 800, between 1 and 700, between 1 and 600, between 1 and 500, between 1 and 400, between 1 and 300, between 1 and 200, between 1 and 100, between 10 and 900, between 20 and 900, between 30 and 900, between 40 and 900, between 50 and 900, between 60 and 900, between 70 and 900, between 80 and 900, between 90 and 900, between 100 and 900, between 200 and 900, between 300 and 900, between 400 and 900, or between 500 and 900.

In certain embodiments, r is between 1 and 1,400, between 1 and 1,000, between 1 and 500, between 1 and 200, between 1 and 100, between 1 and 90, between 1 and 80, between 1 and 70, between 1 and 60, between 1 and 50, between 1 and 40, between 1 and 30, between 1 and 20, or between 1 and 10.

In certain embodiments, k is between 1 and 1,400, between 1 and 1,000, between 1 and 500, between 1 and 200, between 1 and 100, between 1 and 90, between 1 and 80, between 1 and 70, between 1 and 60, between 1 and 50, between 1 and 40, between 1 and 30, between 1 and 20, or between 1 and 10.

In certain embodiments, j is 0.

In certain embodiments, j is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In certain embodiments, R' is an aryl group selected from naphthyl and phenyl. In other embodiments, R ' is selected from the group consisting of 4,4' -diphenylmethane, 3' -dimethylphenyl, 3' -dimethyl-diphenylmethane, 4,6' -xylylene, and p-phenylene.

In certain embodiments, R' is C ₂ -C ₁₂ Alkylene or C ₅ -C ₁₂ Cycloalkyl groups. In certain embodiments, R 'is selected from the group consisting of 4,4' -dicyclohexylmethane, cyclohexyl, 3, 5-trimethylcyclohexyl, and 2, 4-trimethylhexamethylene.

In certain embodiments, R' is a polymer fragment or oligomer fragment selected from the group consisting of: polypropylene oxide, polypropylene oxide-containing chains, polypropylene oxide-rich chains, polytetrahydrofuran-containing chains, polytetrahydrofuran-rich chains, polyethylene oxide-containing chains, polyethylene oxide-rich chains, copolymers of polyethylene oxide and polypropylene oxide, polydimethylsiloxane-containing chains, polydimethylsiloxane-rich chains, polycaprolactone-containing chains and polycaprolactone-rich chains, oligopeptides-containing chains, oligopeptides, oligosaccharides, oligosaccharide-containing chains, oligosaccharide-rich chains, oligomers or copolymers of polymers and addition polymers, and combinations thereof.

In certain embodiments, R' "is a polymer fragment or oligomer fragment selected from the group consisting of: polypropylene oxide, polypropylene oxide-containing chains, polypropylene oxide-rich chains, polytetrahydrofuran-containing chains, polytetrahydrofuran-rich chains, polyethylene oxide-containing chains, polyethylene oxide-rich chains, copolymers of polyethylene oxide and polypropylene oxide, polydimethylsiloxane-containing chains, polydimethylsiloxane-rich chains, polycaprolactone-containing chains and polycaprolactone-rich chains, oligopeptides-containing chains, oligopeptides, oligosaccharides, oligosaccharide-containing chains, oligosaccharide-rich chains, oligomers or copolymers of polymers and addition polymers, and combinations thereof.

Additional embodiments regarding formula (II) are the same as those provided herein with reference to formula (I) or any other formula.

In certain embodiments, the polymer of the present invention is selected from the group consisting of polymers of formula (III):

-{-T-CO-NH-R'-NH-CO-} _X (formula III)

Wherein the method comprises the steps of

T is { - (O- (CH) ₂ ) _j -CHR ₁ -CO) _r -(O-CHCH ₃ -CH ₂ -) _m -O-(CO-CHR ₁ -(CH ₂ ) _j -O-) _k } _p ，

p is an integer between 1 and 100,

each r and k independently of the other is an integer between 1 and 500,

m is an integer between 2 and 100,

each j is independently an integer between 0 and 10,

R ₁ is H or C ₁ -C ₁₂ Alkyl group, and

x is an integer defining the number of repeating units in the polymer of the invention, x can be between 1 and 300.

All embodiments relating to formula (I) and formula (II) and all embodiments provided herein with reference to formula (I) and formula (II) are also equally relevant to formula (III).

In certain embodiments, the polymer of the present invention is selected from polymers of formula (IV):

HOOC-T-COOH (formula IV)

Wherein the method comprises the steps of

p is an integer between 1 and 100,

each r and k independently of the other is an integer between 1 and 500,

m is an integer between 2 and 100,

j are each independently an integer between 0 and 10, and

R ₁ is H or C ₁ -C ₁₂ An alkyl group.

All embodiments provided with respect to and herein with reference to formulae (I) and (II) and (III) are also equally relevant to formula (IV).

In certain embodiments, the polymer of the present invention is selected from the group consisting of polymers of formula (V):

-{-T-CO-NH-R'-CO-NH-R'-NH-CO-R”'-CO-NH-R'-NH-CO-} _z (V)

Wherein the method comprises the steps of

Each R' is independently selected from C ₂ -C ₁₂ Alkylene, C ₅ -C ₁₂ Cycloalkyl, cycloalkyl-containing groups, aryl-containing groups, polymer fragments, oligomer fragments,

z is an integer defining the number of repeating units in the polymer of the invention, z may be between 1 and 300,

p is an integer between 1 and 100,

each r and k independently of the other is an integer between 1 and 500,

m is an integer between 2 and 100,

j are each independently an integer between 0 and 10, and

R ₁ is H or C ₁ -C ₁₂ An alkyl group.

All embodiments provided with respect to and herein with reference to formulae (I) and (II) and (III) and (IV) are also equally relevant to formula (V).

In certain embodiments, each of the polymers of the present invention may be chain extended or coupled by an extender of formula (VI):

l' -OC-R "-CO-L (formula VI)

Wherein the method comprises the steps of

R' is selected from: c (C) ₀ -C ₁₂ Alkylene group, the C ₀ -C ₁₂ Alkylene groups are optionally substituted with one or more hydroxyl groups and/or carboxylic acid groups and/or amine groups; c (C) ₂ -C ₁₀ An olefin; c (C) ₅ -C ₁₂ Cycloalkyl group, the C ₅ -C ₁₂ Cycloalkyl is optionally substituted with one or more hydroxyl groups and/or carboxylic acid groups and/or amine groups, aryl-containing groups; and is also provided with

L and L' independently of each other may be selected from hydroxyl (-OH) groups, halogen (e.g., cl, I, br) groups, amine groups, and ester groups.

As used herein, the term "alkyl" refers to any saturated, monovalent unbranched or branched hydrocarbon chain. An alkyl group may be considered to be a "C" containing between 1 and 12 carbon atoms ₁ -C ₁₂ Alkyl "or any longer chain. Non-limiting examples of such alkyl groups include methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-dimethyl-1-butyl, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl. Any one of the alkyl groups may be substituted or unsubstituted, and where substitution is present, the alkyl group may comprise one or two suitable substituents selected from halogen, -OH, amine (primary, secondary or tertiary), carboxylic acid and others.

When an alkyl chain is an intermediate chain fragment, the alkyl chain is referred to as an "alkylene" group having any number of carbon atoms. The term "C ₂ -C ₂₀ Alkylene "refers to an intermediate chain hydrocarbon fragment containing between 2 and 20 carbon atoms.

In certain embodiments, unless specifically specified otherwise, in a straight chain, branched chain, or any other arrangement, an alkyl group comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms, with the number of hydrogen atoms depending on the particular arrangement of the carbon chains. In certain embodiments, the alkyl group contains between 1 and 12 carbon atoms. In certain embodiments, the alkyl group comprises between 1 and 20 carbon atoms, between 1 and 10 carbon atoms, between 1 and 5 carbon atoms, or between 5 and 15 carbon atoms.

"cycloalkyl" refers to a single or multiple rings containing carbon and hydrogen atoms and having no unsaturation. Cycloalkyl groups may contain between 5 and 20 carbon atoms and may be of a monocyclic structure such as cyclopentyl, cyclohexyl and cycloheptyl (or equivalent cycloalkylene moieties thereof) or a polycyclic structure, and may be unsubstituted or substituted with one or more suitable substituents. In certain embodiments, a cycloalkyl group is a mono-or bicyclic ring comprising from 3 to 6 carbon atoms. A "cycloalkyl-containing group" is any group comprising or in combination with a cycloalkyl group as defined herein.

As used herein, "aryl" means a monocyclic or polycyclic aromatic group containing carbon and hydrogen atoms. Examples of suitable aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7, 8-tetrahydronaphthyl. The aryl group may be unsubstituted or substituted with one or more suitable substituents. In certain embodiments, an aryl group is a single ring comprising 6 or 10 carbon atoms. In certain embodiments, aryl is naphthyl or phenyl or any substituted form thereof. An "aryl-containing group" is any group comprising or in combination with an aryl group as defined herein.

In certain embodiments, the aryl group is a "heteroaryl" group. Heteroaryl groups include monocyclic or polycyclic aromatic rings as defined herein and one to three heteroatoms selected from nitrogen, oxygen and sulfur. Such heteroaryl groups may be selected, for example, from pyridinyl, pyridazinyl, pyrimidinyl (pyrimidyl), pyrazolyl (pyrazyl), triazinyl, pyrrolyl, pyrazolyl (pyrazolyl), imidazolyl, (1, 2, 3) -triazolyl and (1, 2, 4) -triazolyl, pyrazinyl, pyrimidinyl (pyrimidyl), tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, furanyl, thienyl, isoxazolyl and oxazolyl. In certain embodiments, a heteroaryl group is a single ring comprising between 2 and 5 carbon atoms and 1 to 3 heteroatoms.

As used herein, an "ester group" is generally of formula R _y -OC(O)-R _x Or R is _y -C(O)-OR _x Wherein R is _x And R is _y Each of which is independently a point of attachment, R, in a compound of the invention _x And R is _y May be the same or different carbon chains, optionally alkyl groups or alkylene groups as specified or defined herein. In certain embodiments, the ester group is a group that is the product of a hydroxy-alkyl, hydroxy-phenyl, hydroxy-benzyl or substituted hydroxy-alkyl, substituted hydroxy-phenyl or substituted hydroxy-benzyl with an alkyl-acid, aryl-acid, including activated ester groups, such as tosyl groups, mesyl groups, or related activated groups.

In certain embodiments, the polymers of the present invention are selected from polymers having a PO/CL ratio in the range of from about 0.05 to about 100, in the range of from about 0.1 to about 30, or in the range of from about 0.2 to about 10.

In certain embodiments, the polymers of the present invention are selected from polymers having a PO/CL ratio of between about 0.1 and about 30, or between 0.1 and 20, or between 0.1 and 10, or between 0.1 and 5, or between 0.1 and 4, or between 0.1 and 3, or between 0.1 and 2, or between 0.1 and 1, or between about 0.2 and about 10.

In certain embodiments, the polymer is a tri-block polymer having a PO/CL ratio of between 0.05 and 8.

In certain embodiments, the PO/CL ratio is between 0.1 and 5, between 0.1 and 4, between 0.1 and 3, between 0.1 and 2, between 0.1 and 1, between 0.1 and 0.9, between 0.1 and 0.8, between 0.1 and 0.7, between 0.1 and 0.6, between 0.1 and 0.5, between 0.1 and 0.4, between 0.1 and 0.3, between 0.1 and 0.2, between 0.2 and 5, between 0.3 and 5, between 0.4 and 5, between 0.5 and 0.6 and 5, between 0.7 and 5, between 0.8 and 5, between 0.9 and 5, between 1 and 5, between 2 and 5, between 3 and 5, or between 4 and 5.

In certain embodiments, the tri-block polymers of the present invention have a molecular weight between 1,000da and 200,000 da. In some embodiments of the present invention, in some embodiments, the tri-block polymer is selected to have a molecular weight of between 2,000 and 200,000, between 2,000 and 190,000, between 2,000 and 160,000, between 2,000 and 150,000, between 2,000 and 140,000, between 2,000 and 130,000, between 2,000 and 100,000, between 2,000 and 110,000, between 2,000 and 100,000, between 2,000 and 80,000, between 2,000 and 75,000, between 2,000 and 70,000, between 2,000 and 65,000, between 2,000 and 60,000, between 2,000 and 130,000, between 2,000 and 100,000, between 2,000 and 60,000, between 1,000 and 1,000, between 2,000 and 1,000, between 1,000 and 1,000, between 2,000 and 1,000, between 1,000 and 100,000, between 1,000 and 1,000, between 2,000 and 0,000, between 1,000 and 1,000, between 1,000 and 0,000, between 1,000 and 100,000, between 1,000 and 1,000, between 1,000 and 60,000.

In certain embodiments, the tri-block polymer is selected to have a molecular weight of 165,320da, 86,660da, 82,660da, 62,280da, 60,440da, 47,330da, 43,330da, 40,760da, 39, 460 da, 32,640da, 30,220da, 23,732da, 23, 6615 da, 22,760da, 21,380da, 19, 730 da, 17, 630 da, 15,866da, 14,920da, 14,856da, 11,866da, 11,690da, 9,752da, 8, 328 da, 7,933da, 5,964da, 5,876da, or 3,938 da.

In certain embodiments, the tri-block is a polymer of formula (I) wherein x is between 2 and 300.

In certain embodiments, the tri-blocks of the present invention are polymers having a PO/CL ratio between 0.05 and 8. In certain embodiments, the ratio is between 0.1 and 5, between 0.1 and 4, between 0.1 and 3, between 0.1 and 2, between 0.1 and 1, between 0.1 and 0.9, between 0.1 and 0.8, between 0.1 and 0.7, between 0.1 and 0.6, between 0.1 and 0.5, between 0.1 and 0.4, between 0.1 and 0.3, between 0.1 and 0.2, between 0.2 and 5, between 0.3 and 5, between 0.4 and 5, between 0.5 and 5, between 0.6 and 5, between 0.7 and 5, between 0.8 and 5, between 0.9 and 5, between 1 and 5, between 2 and 5, between 3 and 5, or between 4 and 5.

In certain embodiments, the tri-blocks of the present invention are polymers having between 10 and 2,000 caprolactone units. In certain embodiments, the number of caprolactone units is between 10 and 2,000, between 10 and 1,000, between 10 and 900, between 10 and 800, between 10 and 700, between 10 and 600, between 10 and 500, between 10 and 400, between 10 and 300, between 10 and 200, between 10 and 100, between 10 and 350, between 10 and 170, between 10 and 113, between 10 and 85, between 10 and 68, between 10 and 37, between 10 and 17, between 26 and 520, between 26 and 260, between 26 and 173, between 26 and 130, between 26 and 104, between 26 and 52, between 35 and 690, between 35 and 345, between 35 and 230, between 35 and 173, between 35 and 138, between 35 and 69, between 69 and 1380, between 69 and 690, between 69 and 460, between 69 and 345, between 69 and 276, or between 69 and 138.

In certain embodiments, the number of caprolactone units is selected from 1380, 690, 520, 460, 345, 340, 276, 260, 230, 173, 170, 138, 130, 113, 104, 85, 69, 68, 52, 35, 34, 26, and 17.

In certain embodiments, the number of PPO units in the tri-block polymer according to the present invention is 34, 52, 69 or 138.

In certain embodiments, the tri-block polymer according to the present invention is selected from those listed in table 1 below:

table 1: tri-block polymers according to the invention

Also provided are polymers according to the present invention, which are one or more of the polymers listed in table 1. In certain embodiments, the polymer is selected from polymers numbered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28. In certain embodiments, the polymer is polymer number 1, or number 2, or number 3, or number 4, or number 5, or number 6, or number 7, or number 8, or number 9, or number 10, or number 11, or number 12, or number 13, or number 14, or number 15, or number 16, or number 17, or number 18, or number 19, or number 20, or number 21, or number 22, or number 23, or number 24, or number 25, or number 26, or number 27, or number 28. In other embodiments, the polymer is selected from polymers number 1, and/or number 2, and/or number 3, and/or number 4, and/or number 5, and/or number 6, and/or number 7, and/or number 8, and/or number 9, and/or number 10, and/or number 11, and/or number 12, and/or number 13, and/or number 14, and/or number 15, and/or number 16, and/or number 17, and/or number 18, and/or number 19, and/or number 20, and/or number 21, and/or number 22, and/or number 23, and/or number 24, and/or number 25, and/or number 26, and/or number 27, and/or number 28.

In certain embodiments, the polymer is a polymer in table 2 below.

The polymers according to the invention are prepolymerized, chain extended and high molecular weights are obtained. The polymer may optionally be crosslinked. To increase the molecular weight of the resulting polymer, the blocked ABA tri-block or AB di-block (which may be blocked with hydroxyl groups, amine groups, thiol groups or carboxylic acid groups) is chain extended using the following: difunctional compounds such as diisocyanates, dicarboxylic acid compounds or derivatives of dicarboxylic acids such as diacyl halides, and any other groups capable of reacting with the end groups of the ABA tri-block or AB di-block. The products formed by the reaction of a chain extender, coupling agent or cross-linker with an ABA tri-block or AB di-block according to the invention will depend on the chemical nature of the nucleophilic (or electrophilic) moiety (usually terminal) on the ABA tri-block or AB di-block (or related multiple di-blocks) and the electrophilic (or nucleophilic) moiety on the chain extender, coupling agent or cross-linker. The reaction products can vary widely to produce different moieties such as urethane groups, ester groups, urea groups, and amide groups, among many others. For example, in the case of ABA-triblock (hydroxyl terminated) reaction with diisocyanate chain extender, the product is a urethane chain extended polymer. In the event of termination of the amine groups, the ABA-triblock is reacted with a diisocyanate chain extender, the product being urea. In the case of a carboxylic acid group termination, the ABA tri-block (which may be converted to an anhydride or acyl halide) is reacted with an amine or isocyanate terminated chain extender, coupling agent or cross-linking agent, the product being an amide. In certain embodiments, the nucleophilic-terminated tri-blocks are chain-extended with a diisocyanate compound to produce the chain-extended polymers according to the present invention, however the chemical methods as explained above may vary greatly.

In the case of structures such as films and fibers, chain extenders are used to provide the tri-block with a greater molecular weight, thus enhancing mechanical properties and structural integrity.

In the case of gels, liquid polymers and/or viscous solutions, the chain extender, coupling agent or cross-linking agent not only provides high molecular weight, viscosity control and structural integrity, but also provides water solubility/dispersibility consistent with the solubility and/or dispersibility of these polymers in water and delivers these polymers to sites within the patient. Thus, chain extenders and coupling agents can be used to provide a number of benefits without using methods of shortening the a block that can interfere with beneficial morphological and mechanical effects.

In addition to being chain extended or coupled, the polymers according to the invention may also be crosslinked. The crosslinking agent may be similar to the chain extender and coupling agent used in the present invention except that the crosslinking agent comprises at least three reactive functional groups as compared to chain extenders and coupling agents comprising only two reactive functional groups.

In certain aspects of the invention hereby disclosed, the a segments present in the ABA tri-block or AB di-block may contain not only degradable components, but also components intended to cause the polymer to have further advantageous features. This can be exemplified by reacting the PPO B fragments not only with biodegradable components such as lactones, e.g. caprolactone, but also with e.g. lactams, wherein the amide groups are incorporated into the polymer backbone. The biodegradable component and the second component, which may also be biodegradable, may be incorporated into the chain sequentially or together.

In certain aspects of the invention, the chain extender, coupling agent or crosslinking agent may comprise components intended to cause the polymer to have additional advantageous characteristics.

In certain aspects, the chain extender and the coupling agent may have more than two reactive functional groups, only two of which are reactive under the conditions of the chain extension or coupling reaction. The remaining unreacted reactive functional groups may remain unreacted, rendering the final polymer with additional advantageous properties, or may react under other conditions, rendering the chain-extended or coupled polymer crosslinked, or enabling covalent binding of the polymer to another molecule, such as a drug. This staged approach may also be advantageous when making the final product comprised of the polymer of the present invention, taking advantage of the thermoplastic nature of the polymer to crosslink the polymer only at a later stage. It may also enable the binding of bioactive molecules later in time and/or at specific regions of the products formed from the polymers of the present invention.

In certain aspects, ABA tri-blocks and AB di-blocks may be terminated with one or two double bonds that are capable of reacting therebetween to polymerize and/or crosslink the polymers of the present invention. The polymerization and/or crosslinking reaction may follow any known polymerization mechanism, and the reaction may be triggered by any factor capable of initiating the reaction. In the case of free radical polymerization reactions, the reaction can be initiated using free radical catalysts such as Benzoyl Peroxide (BPO) or Azobutyronitrile (AIBN), among many others, or by ultraviolet radiation, in which case the corresponding photoinitiator will be added to the system. In certain embodiments, the reaction between c=c terminated tri-or di-blocks may be achieved by reacting them via other mechanisms, such as michael addition reactions, typically using difunctional amines or thiols. Any mechanism and pathway may be used alone or in combination with other, as well as when tri-blocks and/or di-blocks are used, as well as in the case of combinations thereof.

In certain aspects of the invention disclosed herein, the polymer may be used to make fibers for: in various applications, for example in the biomedical field, in diverse fields such as medical textiles, in many medical devices, implants and prostheses, in wound closure sites, and many others. In certain embodiments, the polymers disclosed herein can be used to make sutures and staples.

The polymers of the present invention can be manufactured into fibers of various thicknesses and lengths. Fibers are produced that cover a wide range of diameters, typically in the range of 100 microns (5-0 USP size) to 600 microns (2 USP size). Fibers having smaller and larger diameters can be similarly produced. Fibers produced based on the polymers of the present invention have strengths of hundreds of MPa, typically between 300MPa and 600 MPa.

Accordingly, the present invention also provides a polymeric fiber comprising any one of the materials of the present invention or any combination thereof.

Medical devices and implants comprising at least one polymeric material according to the present invention are also provided. In certain embodiments, the medical device is a suture that retains a substantial portion of its initial strength after a period of time that can be determined by the composition of the polymer of the present invention. In certain embodiments, the medical device is a suture that retains a substantial portion of its initial strength over a period of three or four months and biodegrades over a period of six to nine months.

It is a further object of the present invention to provide biodegradable polymeric films, each film comprising a material according to the present invention.

Also provided is an apparatus in a form selected from the group consisting of: films, fibers, filaments, webs, membranes (membranes), rods, coatings, woven fabrics, non-woven structures (non-woven structures) or gels.

In certain embodiments, the device is in a form selected from the group consisting of: medical textiles, medical devices, implants, prostheses, wound healing devices, coatings, sutures, meshes, and staples.

The present invention also contemplates biodegradable polymeric objects primarily used in the biomedical field, having different geometries such as, but not limited to, rods, plates, spheres, and cylinders, all covering a wide range of sizes.

Biodegradable polymeric materials of the present invention are also provided for use as coatings for medical devices, wherein the medical device may be a polymeric material, a metallic material, a ceramic material, or any other material.

It is a further object of the present invention to provide polymeric materials for use as metallic medical devices such as stents, metallic portions of heart valves, and many other coatings.

Biodegradable polymeric materials of the present invention are also provided for use as covers for devices such as metal stents, whereby different types of covered stents are formed using the polymers of the present invention.

Biodegradable polymeric materials of the present invention in fiber construction are also provided.

It is a further object of the present invention to provide polymeric materials for use as wound closure devices, such as sutures and staples, which may be produced in a variety of compositions, each of which is suitably configured or tailored for a particular application, based inter alia on the strength, flexibility and biodegradability of the polymeric material.

Thus, also contemplated are medical devices, elements or devices comprising or consisting of at least one tri-block or di-block polymer of the present invention.

In certain embodiments, sutures made from a polymer selected from the group consisting of a polymer of formula I or formula II or formula III or formula IV or formula V or a polymer in table 1 are provided. Sutures made from the materials of the present invention exhibit high tensile strength in vivo, supporting the wound during the healing period, while exhibiting modulated degradation. In addition, the suture is easy to handle, provides optimal knot security and is capable of retaining a layer of tissue while knotting without being detrimental to the tissue. In addition, sutures are resistant to in vivo shrinkage and are absorbed with minimal or no tissue reaction after serving their purpose.

Also provided are staples made from a polymer selected from the group consisting of a polymer of formula I or formula II or formula III or formula IV or formula V or a polymer in table 1 for medical use.

The invention also provides a suture or staple according to the invention for use in a surgical procedure of a human or non-human subject.

In another aspect, the invention provides a suture for use in surgical procedures such as cosmetic surgery, cosmeceutical surgery, orthopedic surgery, soft tissue fixation, wound closure, the suture being in the form of a single, uninterrupted, flexible, elongate wire comprising a material according to formula I or formula II or formula III or formula IV or formula V or a polymer in table 1.

In certain embodiments, the suture is a monofilament suture made from the single strand material of the present invention.

In other embodiments, the suture is a multifilament suture made from a plurality of filaments, each filament comprising the material of the present invention, which may be the same or different. When a multifilament suture is involved, individual filaments may be twisted or braided together to provide greater tensile strength, pliability, and flexibility.

In certain embodiments, the sutures or medical devices or elements of the present invention may be coated with at least one coating material to increase suture handling characteristics, degradability, in vivo stability, and other properties. The at least one coating material may be selected from active materials and inactive materials. In certain embodiments, the active material is selected from a variety of bioactive agents. Exemplary bioactive agents include, for example, anticoagulants, such as heparin and chondroitin sulfate; fibrinolytics (fibrinolytics), such as tPA, plasmin, streptokinase, urokinase and elastase; steroidal and non-steroidal anti-inflammatory agents such as hydrocortisone, dexamethasone, prednisolone, methylprednisolone, promethazine, aspirin, ibuprofen, indomethacin, ketorolac, meclofenamic acid, tolmetin; calcium channel blockers, such as diltiazem, nifedipine, verapamil; antioxidants, such as ascorbic acid, carotenes, alpha-tocopherol, allopurinol, trimetazidine; antibiotics, such as thiosemicarbazide and other antibiotics to prevent infection; a prokinetic agent that promotes intestinal motility; agents that prevent collagen cross-linking, such as cis hydroxyproline and D-penicillamine; and agents that prevent degranulation of mast cells, such as disodium cromolyn, among many others.

In addition to the above agents which generally exhibit advantageous pharmacological activity in relation to promoting wound healing or reducing infection or having hemostatic properties, other bioactive agents may be delivered by the polymers of the present invention, including, for example, amino acids, peptides, proteins including enzymes, carbohydrates, growth factors, antibiotics (treating a particular microbial infection), anticancer agents, neurotransmitters, hormones, immunological agents including antibodies, nucleic acids including antisense agents (anti-sense agents), fertility agents, psychotropic agents, and local anesthetics, as well as many additional agents.

In certain embodiments, the inactive material is selected from dyes, polymeric materials, thickeners, agents that affect hydrophilicity, agents that affect lubricity, and other materials.

The present invention provides a wide variety of suture materials that provide the surgeon with a kit selection of sutures that can be personalized and selected for a variety of purposes and that meet specific requirements derived from the type of surgery, the surgical site, the health of the subject being operated upon, and others. While most surgeons prefer to use a particular type of suture, unless the particular circumstances require otherwise, those skilled in the art will know to select a suitable suture of the present invention based on one or more of the following: patient-specific factors such as health status, presence of infection, etc.; healing characteristics of a particular tissue or organ; the time period required for tissue support and the extent of such support; as well as the type of surgical procedure, the severity of the wound, and other parameters related to the expertise of the surgeon.

The polymers of the present invention may be manufactured by any existing manufacturing technique, such as extrusion, compression molding, injection molding, dip coating, solvent casting, any of a number of 3D printing techniques, and if the polymer is to be tailored, it is compatible with the particular manufacturing technique used.

In certain embodiments of the invention, the polymeric material is selected from ABA tri-blocks and AB di-blocks, where a is a biodegradable segment and B is a poly (propylene oxide) segment.

In certain embodiments, the polymeric material is optionally chain extended, coupled, or crosslinked using a chain extender (or linkage), a coupling segment (or linkage), or a crosslinking segment (or linkage), respectively.

In certain embodiments, the polymeric material is optionally chain extended and/or coupled and/or crosslinked.

In certain embodiments, a is a polymer comprising aliphatic ester units.

In certain embodiments, a is a polymer comprising aliphatic ester units derived from hydroxy acid units, related esters of hydroxy acids, or lactones.

In certain embodiments, a is a polymer comprising: lactic acid, lactide, glycolic acid, glycolide, or related aliphatic hydroxycarboxylic acids or aliphatic hydroxycarboxylic acid esters (lactones) selected from the group consisting of: beta-propiolactone, epsilon-caprolactone, delta-glutaryl lactone, delta-valerolactone, beta-butyrolactone, neopentanlactone, alpha-diethylpropiolactone, ethylene carbonate, trimethylene carbonate, gamma-butyrolactone, p-dioxanone, 1, 4-dioxacyclohepta-2-one, 3-methyl-1, 4-dioxane-2, 5-dione, 3-dimethyl-1, 4-dioxane-2, 5-dione; alpha-hydroxybutyric acid, alpha-hydroxyvaleric acid, alpha-hydroxyisovaleric acid, alpha-hydroxycaproic acid, alpha-hydroxy-alpha-ethylbutyric acid, alpha-hydroxyisohexanoic acid, alpha-hydroxy-alpha-methylpentanoic acid, alpha-hydroxyheptanoic acid, alpha-hydroxystearic acid, alpha-hydroxytwenty-four carboxylic acid, cyclic esters of salicylic acid, and mixtures thereof.

In certain embodiments, a comprises poly (glycolic acid), poly (L-lactic acid), poly (D, L-lactic acid), or polycaprolactone, and combinations thereof.

In certain embodiments, the B block comprises a hydroxy, carboxylic acid, or amine terminated polypropylene oxide segment.

In certain embodiments, ABA triblock or AB diblock used in the polymers of the invention are chain extended or coupled using a difunctional compound that reacts with the end capping groups of the triblock or diblock. In certain embodiments, the difunctional compound is a diisocyanate. In certain embodiments, the diisocyanate is Hexamethylene Diisocyanate (HDI).

In certain embodiments, the difunctional chain extender or coupling agent comprises two molecules having the desired functionality and an intermediate molecule linking the two molecules. In certain embodiments, the molecule in the middle connecting the two molecules is a polyoxyalkylene. In certain embodiments, the molecule in the middle that connects the two molecules is a polyester.

In certain embodiments, the polyalkylene oxide is polyethylene oxide, polypropylene oxide, polytetrahydrofuran, and combinations and copolymers thereof.

In certain embodiments, the polyester is polycaprolactone, polylactic acid, polyglycolic acid, and combinations and copolymers thereof.

In certain embodiments, the difunctional compound is a diisocyanate. In certain embodiments, the diisocyanate is Hexamethylene Diisocyanate (HDI).

In certain embodiments, the ABA triblock is crosslinked using a crosslinker having a functionality of three or more.

In certain embodiments, the AB diblock is coupled using a coupling agent having a functionality of three or more. In certain embodiments, ABA triblock is first chain extended and then crosslinked or coupled.

In certain embodiments, the polymers of the present invention have the following structure:

-[-(O-(CH ₂ ) _j -CHR ₁ -CO) _b -(O-CHCH ₃ -CH ₂ -) _m -O-(CO-CHR ₁ -(CH ₂ ) _j -O-) _a -CO-NH-R'-NH-CO]-

wherein the method comprises the steps of

a. b and m are each a positive integer number,

j is a number from 0 to 10,

r' is selected from C ₂ -C ₁₂ Alkylene groups, cycloalkyl-containing groups, aryl-containing groups, 4' -diphenylmethane, toluene, naphthalene, 4' -dicyclohexylmethane cyclohexyl, 3' -dimethylphenyl, 3' -dimethyl-diphenylmethane, 4,6' -xylylene, 3, 5-trimethylcyclohexyl 2, 4-trimethylhexamethylene, p-phenylene, poly (ethylene oxide) -containing fragments, poly (ethylene oxide) -rich chains, polypropylene-rich chains, polytetramethylene-rich chains, polycaprolactone-rich chains, and is also provided with

R ₁ Is H or CH ₃ 。

In certain embodiments, R' is a hexamethylene group (C ₆ Alkylene group), j=4 and R ₁ Is H.

In certain embodiments, the polymers of the present invention have the following general structure:

-(O-(CH ₂ ) _j -CHR ₁ -CO) _r -(O-CHCH ₃ -CH ₂ -) _m -O-(CO-CHR ₁ -(CH ₂ ) _j -O-) _k -CO-NH-R'-NH-CO-R”'-CO-NH-R'-NH-CO-

wherein the method comprises the steps of

r, k and m are each positive integers,

j is a number from 0 to 10,

r' is selected from C ₂ -C ₁₂ Alkylene groups, cycloalkyl-containing groups, aryl-containing groups, 4' -diphenylmethane, toluene, naphthalene, 4' -dicyclohexylmethane, cyclohexyl, 3' -dimethylphenyl 3,3' -dimethyl-diphenylmethane, 4,6' -xylylene, 3, 5-trimethylcyclohexyl, 2, 4-trimethylhexamethylene, p-phenylene, poly (ethylene oxide) -containing fragments and poly (ethylene oxide) -rich chains,

r' "is a polyoxyalkylene chain comprising a fragment selected from the group consisting of: poly (ethylene oxide), poly (ethylene oxide) -co-poly (propylene oxide), poly (ethylene oxide) -rich chains, polypropylene-rich chains, polytetramethylene-rich chains, polycaprolactone, and polycaprolactone-rich chains, and

R ₁ is H or CH ₃ 。

In certain embodiments, the chain extender or coupling agent has the formula:

L-OC-R”-CO-L

wherein the method comprises the steps of

R' is selected from C ₀ -C ₁₂ Alkylene groups, hydroxy-or carboxylic acid-substituted alkylene groups, olefins, cycloalkyl groups, hydroxy-or carboxylic acid-containing cycloalkyl groups or cycloalkyl-containing groups, aryl groups or aryl-containing groups or poly (alkylene oxide) chains comprising poly (ethylene oxide), poly (ethylene oxide) -co-poly (propylene oxide) or (ethylene oxide) -containing or poly (ethylene oxide) -rich chains, and

Each L is selected from hydroxyl, halogen such as Cl, I or Br, or an ester group that can be prepared from a hydroxyl group (e.g., a hydroxy-alkyl, hydroxy-phenyl, hydroxy-benzyl or substituted hydroxy-alkyl group, substituted hydroxy-phenyl group or substituted hydroxy-benzyl group), including an activated ester group such as a tosyl group, a methylsulfonyl group or a related activated group.

In certain embodiments, the PO/CL ratio of the polymers according to this invention ranges from about 0.05 to about 100 or greater, from about 0.1 to 100, from about 0.1 to about 30 or greater, from about 0.1 to about 10, or from about 0.2 to about 10, from about 0.3 to about 10. In certain embodiments, the PO/CL ratio may fall outside of these ranges, depending on the final properties of the polymer desired.

As used herein, the term "pre-polymerized" is used to describe polymers according to the invention that have been fully polymerized prior to use, e.g., prior to being introduced into or administered to a patient to be treated. The pre-polymerized polymer according to the invention is in contrast to a polymer that can be polymerized in situ, i.e. in the patient at the site of action. The pre-polymerized polymers of the present invention are used to produce both pre-formed structures, such as compositions having one, two or three dimensional structures, such as fibers, films, webs, coatings, films, cylinders, spheres, rods, blocks, tubes, beads, foam or rings, and the like, and related structures, and non-pre-formed compositions; such as reactive precursors, typically monomeric or oligomeric, sprays, gels, liquid polymers, viscous solutions and dispersions, and others.

The term "crosslinked" or "crosslinking agent" is used to describe agents that are typically trifunctional or more, covalently bond ABA tri-blocks or AB di-blocks to other tri-blocks, di-blocks, or other moieties in the polymers of the present invention. As used herein, a crosslinking agent refers to a chemical compound that typically contains at least three (3) reactive moieties, e.g., nucleophilic and/or electrophilic moieties or moieties such as double bonds that can react and crosslink a polymer. In certain embodiments, the crosslinking agent according to the present invention has at least three moieties of the same type, such as nucleophilic moieties, electrophilic moieties, or moieties that initiate free radicals, in order to facilitate the reaction of the crosslinking agent with the tri-block and di-block according to the present invention. In many aspects, the crosslinking agent is associated with a chain extender in the present invention, except that the chain extender comprises only two reactive moieties, while the crosslinking agent comprises at least three reactive moieties.

Exemplary cross-linking agents that may be used in the present invention include the following: the crosslinker comprises a mixture of at least three isocyanate moieties such as isocyanurates and a number of other, or reactive moieties, such as carboxylic acid and hydroxyl groups (examples are citric acid, and a number of others) and amine groups and combinations thereof (examples are selected amino acids and a number of oligopeptides, or a number of oligomers comprising a plurality of groups capable of reacting with the end groups of the triblock and diblock, such as an oligomer of acrylic acid). Alternatively, the triblock and diblock may be capped with isocyanate groups, whether or not the end groups are OH, COOH, NH ₂ Or SH. This can be achieved by reacting the triblock or diblock with a diisocyanate, such as HDI, to produce a macromolecular diisocyanate (macroodiiscyanate) capable of reacting with the compound. In the compounds, any triol or greater, any triacid or greater, any triamine or greater than triamine, and trithiols and greater than trithiols, and combinations thereof, produce polymers according to the present invention.

The reaction of the AB di-block with the crosslinking agent may produce a star-shaped molecule, or in other cases a different structure, such as a comb polymer, for example, but not the crosslinking system itself. Since the AB di-block will typically contain only one reactive moiety per molecule (except in the case where one of the two blocks contains a blocking group that can be removed following initial formation of the AB di-block and then reacted), the use of a cross-linking agent will result in a predetermined structure, such as a star or comb molecule. The inclusion or incorporation of additional moieties in the di-block with which the crosslinker can react will result in a more precise (elabelate) crosslinking system similar to that produced with the ABA tri-block of the present invention.

The terms "non-crosslinked", "substantially non-crosslinked", "crosslinked" or "substantially crosslinked" are used to describe polymers according to the present invention that exhibit or exhibit substantially no crosslinking, or are substantially crosslinked in other embodiments. The polymers according to the invention are successful in wound closure areas, such as sutures and staples, as degradable reinforcing structures, for example as coatings for devices, prostheses and implants in the case of hernia patches (mesh). In certain embodiments of the present invention, the device, prosthesis, and implant may be any type of stent deployed in any system within the body. Polymers according to the invention that are considered to be substantially non-crosslinked include less than about 1.0% crosslinked, less than about 0.5% crosslinked by weight, less than about 0.1% crosslinked by weight, less than about 0.05% crosslinked by weight are advantageously used in the present invention. As used herein, references to crosslinking of 1.0%, 0.5%, 0.1%, etc., refer to the amount by weight of crosslinking agent that may be found in the polymers of the present invention. In other embodiments, the polymers may be crosslinked, i.e., they may contain substantially more crosslinker than 1.0% crosslinker by weight.

The polymer composition according to the invention is optionally chain extended rather than crosslinked, but may be crosslinked in addition to chain extension. It is also possible to produce crosslinked, non-chain-extended polymers according to the invention. In certain embodiments, the polymer is both chain extended and crosslinked. In certain embodiments, the polymer is both coupled and crosslinked. In certain embodiments, the polymer is chain extended, coupled, and crosslinked.

The ABA tri-block or AB di-block used in the polymers of the present invention may be chain extended. The chain extender used is a difunctional compound which reacts with the end capping groups of the triblock to give the chain-extended polymer according to the invention. In certain embodiments, chain extenders having more than two functional groups are used, provided that only two of the functional groups are capable of reacting during the chain extension reaction. The remaining unreacted functional groups may remain intact or will react after the chain extension reaction occurs or under other conditions. In certain embodiments, when the triblock or diblock contains groups capable of reacting with different groups, the reactions may be performed simultaneously.

In the present invention, the amount of chain extender contained in the polymer according to the present invention may vary. Thus, the molar ratio of chain extender to ABA tri-block in the polymers of the present invention varies from about 0.5 to about 2.0 (from about 1:2 to about 2:1), varying from about 0.8 to about 1.2 or about 1.0 based on the moles of difunctional chain extender and the moles of ABA tri-block. In the case of the di-block, the molar ratio of chain extender to AB di-block varies from about 0.25 to about 1.0, or from about 0.5 to 1.0. When used with di-blocks, chain extenders are more precisely described as coupling agents because they couple two di-blocks together to form a di-diblock. It should be noted that in the synthesis of chain-extended polymers, the amount of chain extender that reacts with the difunctional tri-block or di-block to produce the polymer is generally slightly higher than the amount expected to be included in the final synthesized polymer. In certain embodiments, coupling agents having more than two functional groups may be used, provided that only two of the functional groups are capable of reacting during the coupling reaction. The remaining unreacted functional groups may remain intact or will react after the chain extension reaction occurs or under other conditions. In certain embodiments, when the triblock or diblock contains groups capable of reacting with different groups, the reactions may be performed simultaneously.

The chain extender used in the present invention optionally comprises no more than about 1% by weight of a crosslinking compound (such term means a compound comprising at least 3 functional groups that can react with the end-capping groups of the tri-block and is typically present as a byproduct of synthesis or production of the chain extender in the chain extender sample), less than about 0.5% by weight of a trifunctional compound or less than 0.1% by weight. In certain embodiments, it is possible to use difunctional chain extenders which contain as little trifunctional (or higher functionality) compounds as practically possible. In addition, due to both the compositional parameters (compositional parameter) and experimental parameters of the synthetic polymers of the present invention, the occurrence of side reactions that would lead to crosslinking of the polymer is negligible. Of course, in certain embodiments where the crosslinker is used alone (alone or in addition to the chain extender), it is within the scope of the invention to include weight percentages of the crosslinker outside of the weight ranges described above.

In the case of polymers used in structures such as fibers, coatings, webs, and films, the chain extender may be hydrophobic. In the case of polymers used in systems such as hydrogels, water-soluble gels, dispersions or viscous solutions, the chain extender may be highly water-soluble. Suitable water-soluble chain extenders include, for example, polyethylene oxide diisocyanate or poly (ethylene oxide) -co-poly (propylene oxide) copolymer diisocyanate, polyethylene glycol or poly (ethylene oxide) -co-poly (propylene oxide) copolymer chain molecular weights in the range of from about 200 to about 20,000 or more, preferably in the range of from about 600 to about 15,000, even more preferably in the range of from about 600 to about 10,000, and even more preferably in the range of from about 600 to about 3,000. In the case where the preferred embodiment is a water insoluble polymer in liquid form, the chain extender may also be substantially water insoluble. The role of the chain extender in hydrogels and gels and/or viscous solutions according to the invention is to promote enhanced hydrophilicity and in some cases allow water solubility/dispersibility of the polymer and affect its viscosity in an effort to provide a polymer that is easily deliverable to the site in the patient's body and also fine tune the kinetics of degradation, dilution and/or dissolution of these polymers to obtain optimal residence time and enhance the performance of the polymer as a barrier between tissue planes.

In certain embodiments, by utilizing chain extenders rather than cross-linkers, the polymers of the present invention are substantially non-cross-linked and have the following advantages: has excellent structural integrity and properties such as strength and flexibility, which are advantageous for producing fibers.

The term "chain-extended" is used to describe polymers according to the invention in which the base tri-block or di-block is reacted with a difunctional chain extender to increase the molecular weight of the polymer of the invention. In certain preferred embodiments (particularly in the form of fibers and films), the polymers of the present invention are generally non-crosslinked, but rather chain extended to provide polymer chains of sufficiently high molecular weight to enhance the strength and integrity of the final polymer fiber or film composition and to affect the rate of degradation.

Suitable chain extenders for use in the present invention include diisocyanates of the general formula:

O＝C＝N-R'-N＝C＝O

wherein the method comprises the steps of

R' is selected from C ₂ -C ₁₂ Alkylene group, C ₂ -C ₈ An alkylene group, cycloalkyl or cycloalkyl-containing group, aryl or aryl-containing group, 4' -diphenylmethane, toluene, naphthalene, 4' -dicyclohexylmethane, cyclohexyl 3,3' -dimethylphenyl, 3' -dimethyl-diphenylmethane, isophorone, lysine, 4,6' -xylylene, 3, 5-trimethylcyclohexyl, 2, 4-trimethylhexamethylene or p-phenylene.

Equivalents of diisocyanates may also be used as chain extenders in the present invention.

Additional chain extenders may include macromolecular diisocyanates including isocyanate-terminated poly (alkylene oxides) including polymers including poly (ethylene oxide), poly (propylene oxide) and poly (ethylene oxide) -co-poly (propylene oxide) and other isocyanate-terminated polymers.

Additional chain extenders useful in the present invention include, for example, those according to the formula:

L-CO-R”-CO-L

wherein the method comprises the steps of

R' is selected from C ₀ To C ₁₂ Alkylene group, C ₂ To C ₈ Alkylene groups, hydroxy-or carboxylic acid-substituted alkylene groups, olefins, cycloalkyl groups, hydroxy-or carboxylic acid-containing cycloalkyl groups or cycloalkyl-containing groups, aryl groups or aryl-containing groups or poly (alkylene oxide) chains comprising poly (ethylene oxide), poly (ethylene oxide) -co-poly (propylene oxide) or other poly (ethylene oxide) -rich chains, and

each L is independently a hydroxyl, halogen, such as Cl, I, or Br, or an ester group that may be prepared from a hydroxyl group (e.g., a hydroxy-alkyl, hydroxy-phenyl, hydroxy-benzyl, or substituted hydroxy-alkyl group, substituted hydroxy-phenyl group, or substituted hydroxy-benzyl group), including an activated ester group such as a tosyl group, a methanesulfonyl group, or a related activated group.

The terms "strength", "mechanical strength", "burst strength" or "sufficient suture retention" describe the advantageous mechanical and/or physical properties of the polymers of the present invention and reflect the following facts for the polymers of the present invention: (typically as fibers or with sufficient mechanical strength to form or behave in a satisfactory medical device, such as, but not limited to, in wound closure areas such as sutures, meshes, and staples).

In certain embodiments, the polymers according to the present invention have ultimate tensile strength values in the range of about 5MPa to 35MPa and elongation at break values typically in the range of about 400% -2,000%. If, for example, stretched and generally oriented to form fibers, the mechanical properties will be significantly higher, as disclosed below. In other embodiments, the elongation at break exhibited by the polymers of the present invention is much less, sometimes about 100%, sometimes about 50%, sometimes 20%, sometimes 5%, sometimes 2%.

The term "structure" is used to describe a polymer according to the invention having a form, size and dimensions determined in vitro. Typically, the form, size and dimensions will not change significantly after being placed in the patient to be treated. In other embodiments of the invention, the structure does change its shape, size, and mechanical properties after being placed in the body. The term structure includes not only flat, surfaced structures (i.e., films) in a conventional manner, but also fibers, cylinders, tubes, coatings, meshes, and other three-dimensional structures that are not substantially altered by the anatomy of the patient in which the structure has been placed.

In certain embodiments of the invention, ABA tri-blocks or AB di-blocks are units that generally comprise aliphatic ester units derived from various monomers as described above and comprise a poly (hydroxy acid) polymer in the a block and a poly (propylene oxide) polymer in the B block. However, the a blocks are generally biodegradable and range in size from one monomeric unit up to about 400 or more monomeric units and range in size from about 4 to about 50 units, from about 6 to about 30 units, or from about 8 to 16 units. The a block is derived from units of caprolactone, glycolic acid, lactic acid or mixtures thereof in the form of caprolactone reactants, glycolide reactants or lactide reactants. The B block is poly (propylene oxide).

The ABA tri-block or AB di-block is terminated with a nucleophilic moiety such as a hydroxyl group or an amine group. Alternatively, these tri-and di-blocks may also be end-capped with carboxylate groups. With nucleophilic end-capping groups where appropriate, ABA tri-blocks or AB di-blocks can be readily chain extended using difunctional electrophilic compounds such as diisocyanates or dicarboxylic acid compounds (or derivatives of dicarboxylic acids such as esters or diacyl halides). The tri-block or di-block is blocked with hydroxyl groups and chain extended with a diisocyanate compound to produce the preferred polymer according to the present invention. In certain embodiments of the invention, the triblock and diblock of the invention are terminated with c=c bonds capable of polymerization. In certain embodiments, only one of the ends of the triblock is terminated with c=c, which enables the triblock to polymerize, producing a polymer of triblock chains having an olefinic backbone and side chains. The end groups of the triblock of the side chain can then be left as such or used to further derivatize the polymer, including crosslinking or conjugation thereof with a suitable and advantageous bioactive molecule.

The polymer of the present invention in a form selected from the group consisting of films, fibers, coatings, webs, and other preformed structures may be a poly (hydroxy-carboxylic acid)/poly (propylene oxide) polymer of the following chemical structure:

and is also provided with

-[-(O-(CH ₂ ) _j -CHR ₁ -CO) _b -(O-CHCH ₃ -CH ₂ -) _m -O-(CO-CHR ₁ -(CH ₂ ) _j -O-) _a -CO-R”-O]-

As defined above.

Part of the

-CO-R”-CO-

May be derived from a number of di-and tricarboxylic acids including, for example, citric, malic and tartaric acids, and a number of others such as oxalic, malonic, succinic, 2, 3-dimethylsuccinic, glutaric, 3-dimethylglutaric, 3-methyladipic, adipic, pimelic, suberic, azelaic, sebacic, 1, 9-nonanedicarboxylic, 1, 10-decanedicarboxylic, 1, 11-undecanedicarboxylic, 1, 12-dodecanedicarboxylic, maleic, fumaric, diglycolic, hydromuconic (hydromuconic acid), and others including equivalents of these acids. These di-and tricarboxylic acids can be used to chain extend ABA tri-blocks under controlled conditions such that crosslinking is substantially prevented. Alternatively, in certain aspects of the invention, the use of a tricarboxylic acid may result in substantial crosslinking.

In the case of dicarboxylic acids comprising additional carboxylic acid groups and/or other polar groups, such as hydroxyl groups, as in the case of citric acid or malic acid, among others, these will tend to enhance the water solubility of the final polymer composition.

Other embodiments according to the present invention relate to polymer compositions having the following general structure:

wherein R, k and m are positive integers, j is 0 to 10, and R '", R' are C ₂ To C ₁₂ Preferably C ₂ To C ₈ An alkylene group, cycloalkyl or cycloalkyl-containing group, aryl or aryl-containing group, 4' -diphenylmethane, toluene, naphthalene,4,4' -dicyclohexylmethane, cyclohexyl, 3' -dimethylphenyl, 3' -dimethyl-diphenylmethane, 4,6' -xylylene, 3, 5-trimethylcyclohexyl, 2, 4-trimethylhexamethylene, p-phenylene or poly (ethylene oxide) -containing or poly (ethylene oxide) -rich chains, R ' "is a difunctional chain, preferably a polyoxyalkylene chain, such as a poly (ethylene oxide), poly (ethylene oxide) -co-poly (propylene oxide) or other poly (ethylene oxide) -rich chain or a poly (propylene oxide) chain or a polycaprolactone chain or diol, diamine or dicarboxylic acid (OH, NH having a variety of molecular weights and compositions which are reactive with isocyanate groups ₂ Or COOH terminated molecule, in certain embodiments, having at least one c=c containing molecule) or ABA tri-block, wherein a is a polyester unit and B is a diol, diamine, dicarboxylic acid or poly (alkylene oxide) containing or poly (alkylene oxide) rich chain and R ₁ Is H or CH ₃ . Examples of such compounds include, for example, OH-terminated glycol molecules, such as ethylene glycol, butylene glycol; OH-terminated polycaprolactone chains with molecular weights ranging from hundreds up to thousands or more (4,000+); poly (propylene glycol), also with molecular weights in the range of hundreds to thousands or more (8000+); OH-terminated polyesters or oligoesters, such as OH-terminated poly (ethylene succinate) or poly (hexamethylene adipate) or polyfunctional diols such as tartaric acid (comprising two OH groups reactive with isocyanate and two carboxylic acid groups which in carboxylate form will act to enhance the overall hydrophilicity of the composition and can be used to provide a material having pH dependent water solubility).

Further examples of such compounds include: amine-containing compounds (preferably, diamines) such as ethylenediamine, hexamethylenediamine; amino acids such as lysine (where two amine groups react, leaving unreacted carboxylic acid groups); and oligopeptides having two reactive amino groups; and many others.

Examples of difunctional carboxylic acid-containing compounds include, for example, oxalic acid, succinic acid, malic acid, adipic acid, sebacic acid or fumaric acid, maleic acid, COOH-terminated polycaprolactones, COOH-terminated polyesters or oligoesters, for example COOH-terminated poly (ethylenesuccinate) or Poly (hexamethylene adipate). Further examples of such compounds include, for example, c=c containing groups such as fumaric acid (trans) and maleic acid (cis), which react via their COOH groups with diisocyanates, leaving unreacted double bonds available for further derivatization by different mechanisms. More preferably, R' is a hexamethylene group (C ₆ Alkylene groups), R' "is poly (ethylene oxide), j is 4, and R ₁ Is CH ₃ . In certain embodiments, the integers r and k are equal.

In various materials according to the present invention that are included in preformed and non-preformed materials such as fibers, films, coatings, webs, viscous solutions, suspensions, and gels, among others, the polymer may include ABA tri-blocks or AB di-blocks as disclosed above that may be chain extended, coupled, and/or crosslinked using hydrophilic or highly water soluble/water dispersible chain extenders or crosslinkers. It is the hydrophilic chain extenders or coupling agents used in the various polymers according to the invention that allow the delivery of these polymer compositions in aqueous solutions.

The following chain extenders or coupling agents may be used to prepare the polymers disclosed herein:

O＝C＝N-R'-N＝C＝O

Wherein the method comprises the steps of

R' is C ₂ To C ₁₂ Preferably C ₂ To C ₈ An alkylene group, cycloalkyl or cycloalkyl-containing group, aryl or aryl-containing group, 4' -diphenylmethane, toluene, naphthalene, 4' -dicyclohexylmethane, cyclohexyl 3,3' -dimethylphenyl, 3' -dimethyl-diphenylmethane, 4,6' -xylylene, 3, 5-trimethylcyclohexyl, 2, 4-trimethylhexamethylene or p-phenylene.

Suitable chain extenders may include water soluble macromolecular diisocyanates including isocyanate-terminated poly (alkylene oxide) diisocyanates or isocyanate-terminated polymers comprising poly (ethylene oxide), poly (ethylene oxide) -co-poly (propylene oxide) and poly (ethylene oxide) -rich chains, which may be water soluble or non-water soluble, among others.

L-OC-R”-CO-L

wherein R' is C ₀ To C ₁₂ Alkylene group, C ₂ To C ₈ Alkylene groups or hydroxy-or carboxylic acid-substituted alkylene groups, alkene, cycloalkyl, hydroxy-or carboxylic acid-containing cycloalkyl or cycloalkyl-containing groups, aryl or aryl-containing groups or poly (alkylene oxide) chains comprising poly (ethylene oxide), poly (ethylene oxide) -co-poly (propylene oxide) or other poly (ethylene oxide) -containing or poly (ethylene oxide) -rich chains, and each L is a hydroxy, halogen such as Cl, I or Br or an ester group that can be prepared from a hydroxy group (e.g., hydroxy-alkyl, hydroxy-phenyl, hydroxy-benzyl or substituted hydroxy-alkyl groups, substituted hydroxy-phenyl groups or substituted hydroxy-benzyl groups), including activated ester groups such as tosyl groups, mesyl groups or related activated groups. It should be noted that diacids according to this aspect of the present invention may also find use as B blocks in certain ABA tri-blocks and AB di-blocks according to the present invention.

In addition to its specific purpose, the polymers of the present invention may also be used to deliver bioactive compositions to sites within a patient. The polymers of the present invention may be used to particular advantage to deliver bioactive agents that may be used to enhance healing of wounds resulting from surgical procedures, disease states, or other conditions associated with the tissue to be treated.

Exemplary bioactive agents that may be delivered in accordance with the methods of the present invention include, for example, anticoagulants, such as heparin and chondroitin sulfate; fibrinolytes, such as tPA, plasmin, streptokinase, urokinase and elastase; steroidal and non-steroidal anti-inflammatory agents such as hydrocortisone, dexamethasone, prednisolone, methylprednisolone, promethazine, aspirin, ibuprofen, indomethacin, ketorolac, meclofenamic acid, tolmetin; calcium channel blockers, such as diltiazem, nifedipine, verapamil; antioxidants, such as ascorbic acid, carotenes, alpha-tocopherol, allopurinol, trimetazidine; antibiotics, in particular thiosemicarbazide and other antibiotics to prevent infection; a prokinetic agent that promotes intestinal motility; agents that prevent collagen cross-linking, such as cis hydroxyproline and D-penicillamine; and agents that prevent degranulation of mast cells, such as disodium cromolyn, among many others.

In addition to the agents above that generally exhibit advantageous pharmacological activity in connection with promoting wound healing or reducing infection, other bioactive agents may also be delivered by the polymers of the present invention, including, for example, amino acids, peptides, proteins including enzymes, carbohydrates, antibiotics (treating a particular microbial infection), anticancer agents, neurotransmitters, hormones, growth factors, immunological agents including antibodies, nucleic acids including antisense agents, fertility agents, psychotropic agents, and local anesthetics, as well as many additional agents.

The delivery of these agents will depend on the pharmacological activity of the agent, the site of in vivo activity as well as the physicochemical properties of the agent being delivered, the therapeutic index of the agent, and other factors. One of ordinary skill in the art will be able to readily adjust the physicochemical properties of the polymers of the present invention and the hydrophobicity/hydrophilicity of the agent being delivered in order to produce the intended effect. In this aspect of the invention, the bioactive agent is administered in a concentration or amount effective to produce the intended result. It should be noted that the chemistry of the polymer composition according to the present invention can be modified to accommodate a wide range of hydrophilic and hydrophobic bioactive agents and their delivery to the site of the patient.

The present invention also provides an article of manufacture in a structure selected from the group consisting of: films, patches, fibers, coatings, webs, nonwoven fabrics, nails comprising at least one material according to the present invention.

Brief Description of Drawings

For a better understanding of the subject matter disclosed herein and to illustrate how the subject matter may be implemented in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:

FIGS. 1A-C: surgical sutures degrade too quickly and provide maximum support (polydioxanone) only over a period of 6-8 weeks, and thus do not provide adequate support during the wound healing process in most patients. Fig. 1A provides data on a commercial suture: the loss of tensile strength over time was compared to the total resorption time (total resorption time). Fig. 1B illustrates a clinical evaluation of PDS suture relative to MAXON suture, showing premature degradability. Fig. 1C illustrates a clinical evaluation of PDS suture relative to MAXON suture, showing unsatisfactory knottability.

FIG. 2 provides data for PPCA copolymers containing PPO 2,000 segments, with the length of the outboard PCL block decreasing as the PO/CL ratio increases from 0.1 to 2.0. Due to the similar hydrophobicity of the two components, changing PO/CL only slightly affects the contact angle, which decreases from about 80 degrees for PO/cl=0.1 to about 70 degrees for a PO/CL ratio of 2.0.

Figure 3 provides DSC thermograms of four PPCA copolymers, clearly demonstrating the ability to fine tune the crystallinity of the polymer.

Figure 4 provides mechanical data for both PPCA copolymer and clinically used PDS suture, as determined by performing a Knot Pull test (Knot-Pull test).

Fig. 5 also shows the decrease in mechanical properties of PDS and PPCAs 0.1 and 0.2.

Fig. 6 provides the results of knot pull tests performed on PDS and PPCA 0.1 sutures.

Fig. 7A-B also provide a comparison between PDS,1450MPa and PPCA 0.1 suture young's modulus.

FIG. 8 shows a suture according to the present invention, in this case a PPCA 2,000/0.1 suture.

Detailed description of the embodiments

Synthesis of polymers according to the invention

Typically, the synthesis of the polymers of the present invention is carried out by first synthesizing ABA tri-blocks or AB di-blocks. In this general reaction, the pre-prepared poly (propylene oxide) B block (which may be purchased or synthesized from the original diol and an excess of the appropriate epoxide, depending on the length of the desired block) is preferably reacted with a hydroxy acid or cyclic lactone thereof to produce a low molecular weight ABA tri-block or AB di-block. Basically, a poly (propylene oxide) block, typically capped with hydroxyl groups or, in the case of AB di-blocks, hydroxyl groups at one end and a non-reactive group at the other end, is reacted with a hydroxy acid or cyclic lactone thereof to produce an ABA triblock or AB di-block comprising polypropylene and a biodegradable component capped with hydroxyl groups or other groups.

After ABA triblock or AB diblock formation, the hydroxyl groups at the molecular terminals are reacted with a difunctional chain extender or coupling agent such as a diisocyanate. This reaction produces chain-extended or coupled polymers that are readily used to prepare a variety of biomedical products, such as fibers, coatings, webs, nonwoven fabrics, and films, as well as a variety of related structures, gels, dispersions, suspensions, and viscous solutions of the present invention. In the case of certain polymers, these have sufficiently low molecular weights that they are in liquid form without the need for addition of solvents.

In general, during the first stage of the reaction in which the low molecular weight ABA triblock or AB diblock is formed, the total molecular weight and length of the different segments will be determined by the molecular weight of the poly (propylene oxide) block selected to initiate the reaction, by the moles of hydroxy acid, cyclic lactone of hydroxy acid or related compound reacted with the poly (propylene oxide) block, as well as the catalyst and various experimental parameters such as heat and reaction time. Thereafter, the ABA triblock or AB diblock is chain extended, coupled, and/or crosslinked to produce a polymer comprising the ABA triblock or AB diblock.

The synthesis of the polymers of the present invention includes the use of cyclic esters or lactones of epsilon-caprolactone, lactic acid and glycolic acid. The use of epsilon-caprolactone, lactide or glycolide as reactants will enhance the production of ABA triblock or AB diblock with relatively narrow molecular weight distribution and low polydispersity.

After obtaining the triblock or diblock, the hydroxyl-terminated triblock or diblock is reacted with a diisocyanate, preferably hexamethylene diisocyanate, and chain extended, coupled or crosslinked.

The synthesis of ABA triblock or AB diblock is preferably carried out by a ring opening mechanism whereby the ring opening of epsilon-caprolactone, lactide or glycolide is initiated by the hydroxyl end groups of the poly (propylene oxide) (PPO) chains under the influence of a tin catalyst (typically stannous octoate). At this point, ABA type triblock or AB type diblock are produced, whose molecular weight is a function of both the molecular weight of the central PPO chain and the length of the outer polyester blocks. Typically, the molecular weight of the triblock spans between about 2,000 and about 60,000 (but may be as low as 1,000 or lower and as high as 250,000 or higher). In the case of diblock, the molecular weight may be in the range of as low as several hundred to 50,000 or more. After synthesis of the ABA triblock or ABA diblock, the final polymer is preferably obtained by chain extending the hydroxyl terminated triblock with a difunctional reactant such as isocyanate, most preferably hexamethylene diisocyanate.

The chemical and physical properties of the different polymers will vary as a function of different parameters, the molecular weight of the PPO, the composition, morphology and molecular weight of the polyester segments present along the backbone of particular importance, and the chain extender, coupling agent or cross-linking agent.

This method has several advantageous properties, including:

a rapid, almost quantitative reaction is completed in from 1 to 3 hours;

the reaction is carried out under mild reaction conditions (140 ℃) to minimize side reactions; and

the resulting tri-or di-blocks comprise a narrow polydispersity (typically dp=1.4-1.6 or better).

Structures to be engineered for use in the present invention, such as fibers, coatings, webs, and films, and many others, are prepared by: the polymer according to the invention is first produced and then the product is manufactured via a different manufacturing process, in particular by dissolving the polymer in a suitable solvent such as chloroform, methylene chloride, dioxane, tetrahydrofuran or related organic solvents. For example, the film is preferably prepared by placing a solution comprising the polymer in a mold or an associated container and then allowing the solvent to evaporate. The resulting film is uniform and has a uniform thickness and density. The membrane may be prepared or cut into pieces as prepared for application to a desired site in a patient. In addition to the solvent casting method (solvent cast method) described above, the continuous solvent casting process (continuous solvent cast process) as well as the hot casting method (thermal cast method) or other methods conventionally used in the industry and well known in the art, such as, inter alia, extrusion, can also be used to make different devices according to the present invention, such as fibers, films and other structures. To prepare other three-dimensional structures of the polymer, such as cylinders and related shapes, these may be cast or molded starting with solid polymers using various techniques. Methods for producing these structures using these techniques are well known in the art.

Currently, over 5 tens of millions of laparotomy procedures are performed worldwide each year. Typically, closure of the muscular layer of the abdomen is performed using absorbable sutures that should provide sufficient mechanical support to the tissue until natural healing occurs and scar stability (scar stability) is achieved. Reports in the medical literature describe the normal healing time of this fascia layer as requiring 8 weeks of support to recover 80% of its preoperative burst strength.

Since these tests are performed in healthy subjects, the literature today shows that fascia, which is a majority of patients with immunosuppression, requires significantly more time to heal. For example, a delay of about 35% in fascia wound healing has been reported in liver transplant patients.

Today surgical sutures degrade too quickly and only provide maximum support (polydioxanone) over a period of 6-8 weeks, and thus in most patients they do not provide adequate support during the wound healing process (see fig. 1A-C).

An additional disadvantage of current clinically used sutures such as Maxon and PDS for this indication is their poor knottability, most likely due to their somewhat rigid polymer backbone.

Accordingly, one aspect of the present invention is to develop synthetic, biodegradable sutures that exhibit an adjustable degradation rate that provide prolonged support for closure of the abdominal wall as required to follow all laparotomy procedures, thereby minimizing the risk of post-operative herniation. It is a further object of the present invention to create a suture that is capable of producing a stronger, smaller knot that is better resistant to unraveling (resist unravelling) and preferably produces a safe knot with fewer knots.

The synthesis of these block copolymers follows a two-stage process and can be exemplified by copolymers comprising poly (propylene oxide) (PPO) and poly (caprolactone) (PCL) segments, where the poly (caprolactone) chains produce hard blocks and the poly (propylene oxide) forms soft segments along the copolymerized chains. This copolymer was designated PPCA. First, PCL-PPO-PCL triblock is synthesized by ring-opening polymerization of cyclic epsilon-caprolactone initiated by hydroxyl end groups of PPO chain. The second stage of the reaction involves the use of a difunctional coupling agent, typically Hexamethylene Diisocyanate (HDI), to chain extend the OH-terminated PCL-PPO-PCL triblock so that urethane groups are generated along the polymer backbone. These polymers are known as PPCA. When chain extenders having functionalities above two are used, the polymers obtained are crosslinked.

An important feature of the copolymers developed is their multiblock nature. The chain extension of the tailored triblock allows to combine the desired morphology, mainly derived from the length of the two components of the tri-block, and the enhanced mechanical properties, mainly due to the high molecular weight copolymer obtained after the chain extension step. Thus, each of the two components of the copolymers has specific chemical, physical and biological actions to be performed, and this modular approach provides a broad versatility to the polymerization systems.

Although a rich suture warehouse (arsenal) is available to the surgeon, sutures that successfully treat incisions with a mid-range of healing kinetics are not currently available. Basically, for this frequently encountered clinical scenario, there are several sutures that degrade too fast, such as PGA, P (DL) LA, vicryl and also PDS and Maxon, or there are durable sutures that degrade too slowly, such as those based on P (L) LA and PCL.

Thus, this contradiction in this field must address the large gap that exists between, on the one hand, the increasing clinical demand for biodegradable sutures of intermediate range and, on the other hand, the lack of polymers that clinically can provide a solution to this important wound closure requirement. The lack of suitable sutures that can be successfully performed in these situations has most commonly led to the use of sutures that degrade too quickly, which results in 10% to 20% of the incidence of dangerous post-operative incision hernias.

The polymers disclosed herein can be used to make new biodegradable monofilament sutures for a variety of sites and indications, including solutions that provide this unmet clinical need. More specifically, certain of the polymers of the present invention produce sutures that are capable of retaining a substantial portion of their initial strength over a period of three to four months, which are significantly absorbed over a period of six to nine months.

The "multicomponent" approach leading to this project allows us to vary the various parameters of the copolymerization system quite independently. Thus, the properties of different polymers can be adjusted and balanced by varying the composition, morphology and molecular weight of their different components.

The different triblock is characterized by GPC and NMR to confirm the occurrence of ring-opening polymerization of lactones (typically caprolactone units) initiated by OH end groups of PPO and the composition of the resulting triblock, respectively. This is a critical step, since it is the composition of the triblock that will largely determine its morphology and degradation rate, whereas the high molecular weight polymer obtained after the chain extension (or coupling or crosslinking) reaction is determined by GPC. DSC and XRD analysis were used to elucidate its morphology.

Sutures of different polymers were produced and characterized constitutively and morphologically at time zero, and their mechanical properties were measured.

The in vitro degradation rate of the suture was studied under pseudo-physiological conditions (pseudo-physiological condition) (saline solution, 37 ℃, pH 7.0). These studies included gravity measurements (gravimetric measurement), GPC and DSC analyses and measuring the mechanical properties of the polymer over time. Work has also been directed to assessing the knottability of fibers.

Having generally described the invention, reference is now made to the following examples, which are intended to illustrate preferred embodiments and comparisons, but should not be construed as limiting the scope of the invention as set forth more broadly in the foregoing and in the appended claims.

Synthesis of the polymers of the invention

Aba triblock was synthesized as follows:

polypropylene oxide (PPO, mw=2,000) was dried in vacuo at 80 ℃ overnight. Thereafter, the PPO was cooled to room temperature and dried in vacuo over N ₂ The system is rinsed to break and epsilon caprolactone is then added in the appropriate amount (depending on the desired a block length). The mixture of PPO and epsilon-caprolactone was placed in an oil bath at 140 ℃ and after 2-3 minutes (which is typically required to homogenize the system), stannous octoate (catalyst/lactide molar ratio 1/400) was added. The mixture is then treated with N ₂ The rinse is continued for about 5 minutes, after which the N is removed ₂ And the flask containing PPO and epsilon-caprolactone was capped and stirred in an oil bath at 140 ℃ for 2 hours. At the end of the 2 hour period, the mixture was removed from the oil bath, allowed to cool, dissolved in chloroform and precipitated in diethyl ether. The precipitate was then collected and dried overnight in vacuo at 50 ℃. It was then dissolved in chloroform and the chloroform was evaporated to form a film about 250 microns thick.

2. The polymer was synthesized as follows:

the synthesis of the polymer is accomplished by chain extending the ABA tri-block by reacting the hydroxyl terminated groups of the ABA tri-block with a diisocyanate, typically Hexamethylene Diisocyanate (HDI). The tri-block obtained above was dried under vacuum at 80 ℃ for a period of 2 hours. After a two hour period, vacuum is applied by passing N ₂ Flushing the system to break and addA minimum amount of dry dioxane was added to dissolve the tri-block. The required amount of catalyst was dissolved in dioxane (about 5 ml) and added to the tri-block. 15ml of dry dioxane was introduced into a separating funnel and the required amount of HDI was added (HDI: catalyst molar ratio 5:1), and HDI was typically in a 7% -12% molar excess with respect to the tri-block. Thus, typical tri-block to HDI to catalyst molar ratios are 1.0:1.07:0.2, respectively. After the tri-block was completely dissolved, the HDI solution was added dropwise to the tri-block solution (over a period of 30 minutes). Then, a condenser was connected to the reaction flask to prevent loss of dioxane and the reaction continued for a period of 2.5 hours. The reaction was then removed from the oil bath, allowed to cool and the polymer solution was precipitated with diethyl ether. The precipitated polymer was then collected and dried overnight at 50 ℃. Then, the material was dissolved in chloroform and chloroform was initially evaporated overnight at room temperature, followed by evaporation under vacuum at 40 ℃ for 5 hours to form a film of about 140 μm thickness.

Table 2 below reports the stress at break and modulus values for films representing three polymers of the PPCA copolymer family.

Table 2: stress at break and modulus values for the three PPCA copolymers.

Since PPO is an amorphous polymer with a very low glass transition temperature, by controlling the length of the PCL fragment and thus its crystallinity, a particularly flexible PPCA polymer is produced. On the other hand, by selecting shorter PPO chains and selecting longer and therefore higher crystallinity (more crystalline) PCL blocks, copolymers of higher stiffness and strength are produced.

By controlling the nature and balance between the two essential components present in the copolymer and their respective lengths, the degradation rate is controlled over a wide range of time periods. The copolymerization of the invention can be brought about by extending the tri-block PPO-based chain with hydrophilic chain extenders or coupling or crosslinking agents in the corresponding casesThe system has a controlled degree of hydrophilicity. Examples of this type of copolymer can be made from OCN-HDI- { PEO } _w HDI-NCO, where w represents the number of ethylene oxide units present in the PEO chain.

The fibers of the polymers of the present invention are produced by various techniques such as extrusion and gel spinning.

Figure 4 provides mechanical data for both PPCA copolymer and PDS suture used clinically, as determined by performing a knot pull test. It is evident from the findings that PPCA copolymers with low PO/CL ratios, in particular 0.1 and 0.2, yield well under stress, with a 320MPa threshold, and PPCA 0.4 copolymers are also very close to this lower limit. It is also worth emphasizing that PDS shows a high young's modulus of almost 1.5GPa, whereas PPCA 0.1 and 0.2 exhibit much lower values, namely 755MPa and 330MPa, respectively. As will be shown below, the enhanced flexibility of the PPCA backbone results in PPCA sutures with enhanced knottability.

Fig. 5 also shows the decrease in mechanical properties of PDS and PPCAs 0.1 and 0.2. While PDS sutures currently in clinical use have crossed the 320MPa threshold after 60 days and lost all their strength after three months, PPCA copolymers show significantly different behavior. Of particular interest are PPCA 0.1 and PPCA 0.2, which are maintained at a minimum strength requirement of 320MPa for 300 days and 180 days, respectively.

Fig. 6 provides the results of knot pulling tests performed on PDS and PPCA 0.1 sutures highlighting the significantly superior behavior of PPCA 0.1. While PDS sutures lost all of their strength prematurely (already after eight weeks), PPCA 0.1 sutures also showed a yield strength of about 350MPa after 16 weeks.

Fig. 7A-B also provide a comparison between PDS (1450 MPa) and young's modulus of PPCA 0.1 suture, PPCA 0.1 suture exhibiting (fig. 7A) half the high modulus. This difference in stiffness is believed to be responsible for the enhanced knottability of PPCA 0.1 suture when compared to the knottability of PDS suture, as shown in fig. 7B.

While three small, tight knots are sufficient to tie the PPCA 0.1 suture firmly, a PDS suture requires seven knots. It is also worth emphasizing not only the bulkiness of the knot formed by the PDS suture, but even more important is its tendency to unravel, as clearly shown in fig. 7B.

Suture use is sufficiently verified at low temperatures

ETO cycle to sterilize. The suture is manufactured following a two-stage process, starting with an extruded polymer, then subjected to a cooling step and then stretched substantially to obtain the suture.

After the sutures are manufactured, they are sent to an external source to connect the needle to the sutures to sterilize them and finally package them. Sutures were sterilized using a well-proven low temperature (-32 degrees celsius) ETO cycle. FIG. 8 shows one of the sutures, in this case PPCA 2,000/0.1 suture.

In view of the fact that incorporation of PEO segments along the backbone of aliphatic polyesters is widely used to accelerate degradation of the polyesters, it is entirely unexpected and most surprising that the copolymers of the present invention comprising hydrophobic PPO chains degrade at a similar rate when compared to their PEO-containing counterparts. This is hereby exemplified by a comparison between PPCA2,000/0.1 and its PEO-containing counterpart. After about 100 days of in vitro degradation at 37 degrees, knot pulling tests on both sutures showed a reduction in PPCA2,000/0.1 suture stress yield of about 37% (from about 520MPa to 330 MPa) and a reduction in its PEO-containing counterpart of about 31% (from 480MPa to about 330 MPa).

Samples of this polymer were implanted into rats near the sciatic nerve and degraded over a period of three months.

Animal studies were performed in female rat models and PPCA2,000/0.1 suture was compared to commercially available PDS suture currently in clinical use. After the animals were anesthetized, longitudinal cuts were made in the abdomen and muscles were exposed. The incision was closed with control (PDS) or experimental suture (PPCA 2,000/0.1) and the skin closed with a commercial nylon suture. Transplantation was performed at five time points: 2 weeks, 5 weeks, 8 weeks, 12 weeks and 16 weeks (at each time point 6 rats were sutured with PPC2000/0.1 suture and two rats were sutured with PDS), and the relevant tissues were analyzed histologically. In addition, the suture was visually inspected and its mechanical properties were determined using knot pullout strength and molecular weight.

From the results of preclinical studies, it is evident that PPCA 0.1 suture performed much better than PDS suture used clinically. While PDS sutures weaken rapidly, after 8 weeks, a minimum physiological 320MPa stress has not been maintained, losing all of its strength after 12 weeks. In sharp contrast, PPCA 0.1 suture showed a value of about 400MPa after 12 weeks, only slightly decreased after another four weeks, and a stress yield value of about 370MPa after 16 weeks in the body.

In addition, pathological analysis of the tissue surrounding the suture after 16 weeks of implantation revealed that PPCA 0.1 performed extremely well, causing only minimal inflammatory responses.

It should be understood that the examples and embodiments described above are for the purpose of providing a description of the invention by way of example and should not be construed as limiting the invention in any way. Various modifications and variations that may be made to the foregoing description by one of ordinary skill in the art are also contemplated by the present invention and are intended to be included within the spirit and scope of the present application and the following claims.

Claims

1. A fiber comprising a solid polymer comprising ABA tri-blocks and/or AB di-blocks, wherein a is a biodegradable polyester segment and B consists of a poly (propylene oxide) (PPO) segment, wherein in the polymer the tri-blocks or the di-blocks are chain extended, coupled or crosslinked and wherein the tri-blocks or the di-blocks have a molecular weight between 2KDa and 5,000 KDa.

2. The fiber of claim 1, wherein the molecular weight is between 2,000da and 4,500,000 da.

3. The fiber of claim 1, wherein the biodegradable polyester segments are different.

4. The fiber of claim 1 wherein the polyester is derived from a compound selected from the group consisting of: aliphatic hydroxycarboxylic acids or esters of aliphatic hydroxycarboxylic acids, lactones, di-polyesters, carbonates, anhydrides, orthoesters, and dioxanones.

5. The fiber of claim 4 wherein the compound is selected from the group consisting of lactic acid, lactide, glycolic acid, glycolide, aliphatic alpha-hydroxycarboxylic acids, beta-propiolactone, epsilon-caprolactone, delta-glutaryl lactone, delta-valerolactone, beta-butyrolactone, pivalolactone, alpha-diethylpropiolactone, ethylene carbonate, trimethylene carbonate, gamma-butyrolactone, para-dioxanone, 1, 4-dioxacyclohepta-2-one, 3-methyl-1, 4-dioxane-2, 5-dione, 3-dimethyl-1, 4-dioxane-2, 5-dione, alpha-hydroxybutyric acid, alpha-hydroxyvaleric acid, alpha-hydroxyisovaleric acid, alpha-hydroxy-alpha-ethylbutyric acid, alpha-hydroxyisohexanoic acid, alpha-hydroxy-alpha-methylvaleric acid, alpha-hydroxyheptanoic acid, alpha-hydroxystearic acid, alpha-hydroxyditetradecanoic acid, cyclic esters of salicylic acid, and any combination thereof.

6. The fiber of claim 4 wherein the compound is selected from caprolactone, lactide, glycolide and any combination thereof.

7. The fiber of claim 6 wherein the compound is caprolactone.

8. The fiber of claim 1 wherein a is derived from a compound selected from the group consisting of: beta-propiolactone, epsilon-caprolactone, delta-glutaryl lactone, delta-valerolactone, beta-butyrolactone, pivalolactone, alpha-diethylpropiolactone, ethylene carbonate, trimethylene carbonate, gamma-butyrolactone, p-dioxanone, 1, 4-dioxacyclohepta-2-one, 3-methyl-1, 4-dioxane-2, 5-dione, 3-dimethyl-1, 4-dioxane-2, 5-dione, alpha-hydroxybutyric acid, alpha-hydroxyvaleric acid, alpha-hydroxyisovaleric acid, alpha-hydroxycaproic acid, alpha-hydroxy-alpha-ethylbutyric acid, alpha-hydroxyisocaproic acid, alpha-hydroxy-alpha-methylvaleric acid, alpha-hydroxyheptanoic acid, alpha-hydroxystearic acid, alpha-hydroxyditetradecanoic acid, cyclic esters of salicylic acid, and any combination thereof.

9. The fiber of claim 1, wherein a comprises a poly (hydroxy-carboxylic acid).

10. The fiber of claim 9, wherein the poly (hydroxy-carboxylic acid) is selected from the group consisting of poly (glycolic acid), poly (L-lactic acid) and poly (D, L-lactic acid), polycaprolactone, and any combination thereof.

11. The fiber of claim 1 wherein B is poly (propylene oxide) and each of a comprises poly (caprolactone).

12. The fiber of claim 11, the polymer being chain extended with a diisocyanate.

13. The fiber of claim 1, the polymer having formula (I):

{-[-(O-(CH ₂ ) _j -CHR ₁ -CO) _b -(O-CHCH ₃ -CH ₂ -) _m -O-(CO-CHR ₁ -(CH ₂ ) _j -O-) _a -CO-NH-R'-NH-CO]-} _x formula (I)

Wherein the method comprises the steps of

Each of a and b is independently an integer between 1 and 2,000,

m is an integer between 2 and 1,000,

each j is independently an integer between 0 and 20,

r' is selected from C ₂ -C ₂₀ Alkylene, C ₅ -C ₂₀ Cycloalkyl, C-containing ₅ -C ₂₀ Cycloalkyl groups, aryl-containing groups, polymer or oligomer segments and

x is an integer between 1 and 1,000.

14. The fiber of claim 13, wherein x is between 1 and 900.

15. The fiber of claim 13, wherein a is between 1 and 1,400.

16. The fiber of claim 13, wherein b is between 1 and 1,400.

17. The fiber of claim 13, wherein m is between 2 and 900.

18. The fiber of claim 13, wherein j is 0 or 1.

19. The fiber of claim 13, wherein j is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

20. The fiber of claim 13, wherein R' is an aryl or aryl-containing group.

21. The fiber of claim 20, wherein the aryl group is selected from the group consisting of naphthyl and phenyl, wherein the aryl-containing group comprises naphthyl or phenyl.

22. The fiber of claim 13 wherein R ' is selected from the group consisting of 4,4' -diphenylmethane, 3' -dimethylphenyl, 3' -dimethyl-diphenylmethane, 4,6' -xylylene, and p-phenylene.

23. The fiber of claim 13 wherein R' is C ₂ -C ₁₂ Alkylene or C ₅ -C ₁₂ Cycloalkyl groups.

24. The fiber of claim 13 wherein R 'is selected from the group consisting of 4,4' -dicyclohexylmethane, isophorone, lysine, cyclohexyl, 3, 5-trimethylcyclohexyl, and 2, 4-trimethylhexamethylene.

25. The fiber of claim 13, wherein R' is a polymer segment or an oligomer segment.

26. The fiber of claim 13, wherein j = 0.

27. The fiber of claim 13 wherein R ₁ is-CH ₃ 。

28. The fiber of claim 13 wherein R ₁ is-H.

29. The fiber of claim 13 wherein R' is isophorone or lysine.

30. The fiber of claim 13, wherein j = 0 and R ₁ is-H.

31. The fiber of claim 13, wherein j = 0 and R ₁ is-CH ₃ 。

32. The fiber of claim 13 wherein R' is a hexamethylene group, j=4 and R ₁ is-H.

33. The fiber of claim 1, wherein the polymer has the formula (II):

{-(O-(CH ₂ ) _j -CHR ₁ -CO) _r -(O-CHCH ₃ -CH ₂ -) _m -O-(CO-CHR ₁ -(CH ₂ ) _j -O-) _k -CO-NH-R'-NH-CO-R”'-CO-NH-R'-NH-CO-} _z formula (II)

Wherein the method comprises the steps of

Each r and k independently of the other is an integer between 1 and 2,000,

m is an integer between 2 and 1,000,

each j is independently an integer between 0 and 20,

each R' is independently selected from C ₂ -C ₂₀ Alkylene, C ₅ -C ₂₀ Cycloalkyl, C-containing ₅ -C ₂₀ Cycloalkyl groups, aryl-containing groups, polymer fragments or oligomer fragments, and

each R ₁ Independently of one another, H or C ₁ -C ₁₂ An alkyl group, a hydroxyl group,

z is an integer between 1 and 1,000.

34. The fiber of claim 33, wherein z is between 1 and 900.

35. The fiber of claim 33, wherein r is between 1 and 1,400.

36. The fiber of claim 33, wherein k is between 1 and 1,400.

37. The fiber of claim 33, wherein m is between 2 and 900.

38. The fiber of claim 33, wherein j is 0.

39. The fiber of claim 33, wherein j is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

40. The fiber of claim 33, wherein R' is an aryl or aryl-containing group.

41. The fiber of claim 40 wherein the aryl group is selected from the group consisting of naphthyl and phenyl; and wherein the aryl-containing group comprises a naphthyl or phenyl group.

42. The fiber of claim 33 wherein R ' is selected from the group consisting of 4,4' -diphenylmethane, 3' -dimethylphenyl, 3' -dimethyl-diphenylmethane, 4,6' -xylylene, and p-phenylene.

43. The fiber of claim 33, wherein R' is C ₂ -C ₁₂ Alkylene or C ₅ -C ₁₂ Cycloalkyl groups.

44. The fiber of claim 33 wherein R 'is selected from the group consisting of 4,4' -dicyclohexylmethane, cyclohexyl, 3, 5-trimethylcyclohexyl, and 2, 4-trimethylhexamethylene.

45. The fiber of claim 33, wherein R' is a polymer segment or an oligomer segment.

46. The fiber of claim 45 wherein the polymer or oligomer segments are selected from the group consisting of polypropylene oxide, polytetrahydrofuran, polyethylene oxide, copolymers of polyethylene oxide and polypropylene oxide, polydimethylsiloxanes, polycaprolactone, oligopeptides, oligosaccharides, and combinations thereof.

47. The fiber of claim 45 wherein the polymer or oligomer segments are selected from the group consisting of polypropylene oxide-containing chains, polytetrahydrofuran-containing chains, polyethylene oxide-containing chains, copolymers of polyethylene oxide and polypropylene oxide, polydimethylsiloxane-containing chains, polycaprolactone-containing chains, oligopeptide-containing chains, oligosaccharide-containing chains, and combinations thereof.

48. The fiber of claim 45 wherein the polymer segment or oligomer segment is selected from the group consisting of polypropylene oxide-rich chains, polytetrahydrofuran-rich chains, polyethylene oxide-rich chains, copolymers of polyethylene oxide and polypropylene oxide, polydimethylsiloxane-rich chains, polycaprolactone-rich chains, oligopeptide-rich chains, oligosaccharide-rich chains, and combinations thereof.

49. The fiber of claim 33, wherein R' "is a polymer segment or an oligomer segment.

50. The fiber of claim 49 wherein the polymer or oligomer segments are selected from the group consisting of polypropylene oxide, polytetrahydrofuran, polyethylene oxide, copolymers of polyethylene oxide and polypropylene oxide, polydimethylsiloxanes, polycaprolactone, oligopeptides, oligosaccharides, and combinations thereof.

51. The fiber of claim 49 wherein the polymer or oligomer segments are selected from the group consisting of polypropylene oxide-containing chains, polytetrahydrofuran-containing chains, polyethylene oxide-containing chains, copolymers of polyethylene oxide and polypropylene oxide, polydimethylsiloxane-containing chains, polycaprolactone-containing chains, oligopeptide-containing chains, oligosaccharide-containing chains, and combinations thereof.

52. The fiber of claim 49 wherein the polymer segment or oligomer segment is selected from the group consisting of polypropylene oxide-rich chains, polytetrahydrofuran-rich chains, polyethylene oxide-rich chains, copolymers of polyethylene oxide and polypropylene oxide, polydimethylsiloxane-rich chains, polycaprolactone-rich chains, oligopeptide-rich chains, oligosaccharide-rich chains, and combinations thereof.

53. The fiber of claim 1, wherein the polymer has the formula (III):

-{-T-CO-NH-R'-NH-CO-} _X formula (III)

Wherein the method comprises the steps of

T is {-(O-(CH ₂ ) _j -CHR ₁ -CO) _r -(O-CHCH ₃ -CH ₂ -) _m -O-(CO-CHR ₁ -(CH ₂ ) _j -O-) _k } _p ，

R' is selected from C ₂ -C ₂₀ Alkylene, C ₅ -C ₂₀ Cycloalkyl, C-containing ₅ -C ₂₀ Cycloalkyl groups, aryl-containing groups, polymer fragments or oligomer fragments,

p is an integer between 1 and 100,

each r and k independently of the other is an integer between 1 and 500,

m is an integer between 2 and 100,

Each j is independently an integer between 0 and 10,

R ₁ is H or C ₁ -C ₁₂ Alkyl group, and

x is an integer between 1 and 300.

54. The fiber of claim 1, wherein the polymer has the formula (IV):

HOOC-T-COOH formula (IV)

Wherein the method comprises the steps of

p is an integer between 1 and 100,

each r and k independently of the other is an integer between 1 and 500,

m is an integer between 2 and 100,

j are each independently an integer between 0 and 10, and

R ₁ is H or C ₁ -C ₁₂ An alkyl group.

55. The fiber of claim 1, wherein the polymer has formula (V):

-{-T-CO-NH-R'-CO-NH-R'-NH-CO-R”'-CO-NH-R'-NH-CO-} _z (V)

Wherein the method comprises the steps of

Each R' is independently selected from C ₂ -C ₁₂ Alkylene, C ₅ -C ₁₂ Cycloalkyl, cycloalkyl-containing groups, aryl-containing groups, polymer fragments or oligomer fragments,

x is an integer between 1 and 300,

p is an integer between 1 and 100,

each r and k independently of the other is an integer between 1 and 500,

m is an integer between 2 and 100,

j are each independently an integer between 0 and 10, and

R ₁ is H or C ₁ -C ₁₂ An alkyl group.

56. The fiber of claim 1, wherein the ABA tri-block or AB di-block polymer is chain extended with or coupled with or crosslinked with a difunctional compound.

57. The fiber of claim 56 wherein said difunctional compound is selected from the group consisting of diisocyanates.

58. A fiber according to claim 57, wherein the diisocyanate is Hexamethylene Diisocyanate (HDI).

59. The fiber of claim 56, wherein chain extension or coupling is by an extender of formula (VI):

l' -OC-R "-CO-L type (VI)

Wherein the method comprises the steps of

R' is selected from C ₀ -C ₁₂ Alkylene group, the C ₀ -C ₁₂ The alkylene group is optionally substituted with one or more groups selected from hydroxyl groups, carboxylic acid groups, amine groups; c (C) ₂ -C ₁₀ An olefin; c (C) ₅ -C ₁₂ Cycloalkyl group, the C ₅ -C ₁₂ Cycloalkyl groups are optionally substituted with one or more groups selected from hydroxyl groups, carboxylic acid groups, amine groups, aryl-containing groups; and is also provided with

L and L' are independently selected from each other from hydroxyl, halogen, and ester groups.

60. The fiber of claim 1, the polymer having a PO/CL ratio of between 0.05 and 100.

61. The fiber of claim 60, the polymer having a PO/CL ratio of between 0.1 and 30.

62. The fiber of claim 60, the polymer being a tri-block polymer having a PO/CL ratio of between 0.05 and 8.

63. The fiber of claim 60, wherein the PO/CL ratio is between 0.1 and 5.

64. The fiber of claim 1, wherein the polymer is a tri-block polymer having a molecular weight between 2,000da and 5000,000 da.

65. The fiber of claim 64, wherein the tri-block polymer has a molecular weight between 2,000da and 200,000 da.

66. The fiber of claim 64, wherein the tri-block polymer has a molecular weight of 165,320da, 86,660da, 82,660da, 62,280da, 60,440da, 47,330da, 43,330da, 40,760da, 39, 460 da, 32,640da, 30,220da, 23,732da, 23, 6615 da, 22,760da, 21,380da, 19, 730 da, 17, 460 da, 15,866da, 14,920da, 14, 850 da, 11,866da, 11,690da, 9,752da, 8,928da, 7,933da, 5,964da, 5,876da, or 3,938 da.

67. The fiber of claim 13, wherein the tri-block is a polymer of formula (I), wherein x is between 2 and 300.

68. The fiber of claim 13, the polymer being a tri-block polymer having between 10 and 2,000 caprolactone units.

69. The fiber of claim 33, wherein the tri-block is a polymer of formula (II), wherein z is between 2 and 300.

70. The fiber of claim 33, the polymer being a tri-block polymer having between 10 and 2,000 caprolactone units.

71. The fiber of claim 68, wherein the number of caprolactone units is selected from 1380, 690, 520, 460, 345, 340, 276, 260, 230, 173, 170, 138, 130, 113, 104, 85, 69, 68, 52, 35, 34, 26, and 17.

72. The fiber of claim 70, wherein the number of caprolactone units is selected from 1380, 690, 520, 460, 345, 340, 276, 260, 230, 173, 170, 138, 130, 113, 104, 85, 69, 68, 52, 35, 34, 26, and 17.

73. The fiber of claim 68, wherein the number of PPO units in the tri-block polymer is 34, 52, 69 or 138.

74. The fiber of claim 70, wherein the number of PPO units in the tri-block polymer is 34 or 52.

75. The fiber of claim 70, wherein the number of PPO units in the tri-block polymer is 69 or 138.

76. The fiber of claim 1, the polymer being any one of the following tri-block polymers numbered 1 to 28:

77. the fiber of any of claims 1-76, being in the form of a filament.

78. The fiber of any of claims 1-76, for use in a manufacturing apparatus or object.

79. The fiber of any one of claims 1-76, for use as a wound closure device.

80. The fiber of claim 79, wherein the device is selected from the group consisting of a suture, a mesh, and a staple.

81. A device comprising the fiber according to any one of claims 1 to 77.

82. The device of claim 81, which is a medical device.

83. The device of claim 81 or 82, which is in the form of a mesh, rod, woven fabric or non-woven fabric structure.

84. The device of claim 82, in a form selected from the group consisting of: medical textiles, implants, prostheses, and wound healing devices.

85. The device of claim 82, wherein the medical device is a suture, mesh, or staple.

86. A suture comprising a solid polymer comprising ABA tri-blocks and/or AB di-blocks, wherein a is a biodegradable polyester segment and B consists of a poly (propylene oxide) (PPO) segment, wherein in the polymer the tri-blocks or the di-blocks are chain extended, coupled or crosslinked and wherein the tri-blocks or the di-blocks have a molecular weight between 2KDa and 5,000 KDa.

87. The suture of claim 86, wherein the molecular weight is between 2,000da and 4,500,000 da.

88. The suture of claim 86, wherein the biodegradable polyester segments are different.

89. The suture of claim 86, wherein the polyester is derived from a compound selected from the group consisting of: aliphatic hydroxycarboxylic acids or esters of aliphatic hydroxycarboxylic acids, lactones, di-polyesters, carbonates, anhydrides, orthoesters, and dioxanones.

90. The suture of claim 89, wherein the compound is selected from the group consisting of lactic acid, lactide, glycolic acid, glycolide, aliphatic alpha-hydroxycarboxylic acids, beta-propiolactone, epsilon-caprolactone, delta-glutaryl lactone, delta-valerolactone, beta-butyrolactone, pivalolactone, alpha-diethylpropiolactone, ethylene carbonate, trimethylene carbonate, gamma-butyrolactone, para-dioxanone, 1, 4-dioxacyclohepta-2-one, 3-methyl-1, 4-dioxane-2, 5-dione, 3-dimethyl-1, 4-dioxane-2, 5-dione, alpha-hydroxybutyric acid, alpha-hydroxyvaleric acid, alpha-hydroxyisovaleric acid, alpha-hydroxy-alpha-ethylbutyric acid, alpha-hydroxyisohexanoic acid, alpha-hydroxy-alpha-methylvaleric acid, alpha-hydroxyheptanoic acid, alpha-hydroxystearic acid, alpha-hydroxyditetradecanoic acid, cyclic esters of salicylic acid, and any combination thereof.

91. The suture of claim 89, wherein the compound is selected from caprolactone, lactide, glycolide, and any combination thereof.

92. The suture of claim 91, wherein the compound is caprolactone.

93. The suture of claim 86, wherein a is derived from a compound selected from the group consisting of: beta-propiolactone, epsilon-caprolactone, delta-glutaryl lactone, delta-valerolactone, beta-butyrolactone, pivalolactone, alpha-diethylpropiolactone, ethylene carbonate, trimethylene carbonate, gamma-butyrolactone, p-dioxanone, 1, 4-dioxacyclohepta-2-one, 3-methyl-1, 4-dioxane-2, 5-dione, 3-dimethyl-1, 4-dioxane-2, 5-dione, alpha-hydroxybutyric acid, alpha-hydroxyvaleric acid, alpha-hydroxyisovaleric acid, alpha-hydroxycaproic acid, alpha-hydroxy-alpha-ethylbutyric acid, alpha-hydroxyisocaproic acid, alpha-hydroxy-alpha-methylvaleric acid, alpha-hydroxyheptanoic acid, alpha-hydroxystearic acid, alpha-hydroxyditetradecanoic acid, cyclic esters of salicylic acid, and any combination thereof.

94. The suture of claim 86, wherein a comprises poly (hydroxy-carboxylic acid).

95. The suture of claim 94, wherein the poly (hydroxy-carboxylic acid) is selected from the group consisting of poly (glycolic acid), poly (L-lactic acid) and poly (D, L-lactic acid), polycaprolactone, and any combination thereof.

96. The suture of claim 86, wherein B is poly (propylene oxide) and each of a comprises poly (caprolactone).

97. The suture of claim 96, the polymer being chain extended with a diisocyanate.

98. The suture of claim 86, the polymer having formula (I):

Wherein the method comprises the steps of

Each of a and b is independently an integer between 1 and 2,000,

m is an integer between 2 and 1,000,

each j is independently an integer between 0 and 20,

r' is selected from C ₂ -C ₂₀ Alkylene, C ₅ -C ₂₀ Cycloalkyl, C-containing ₅ -C ₂₀ Cycloalkyl groups, aryl-containing groups, polymer fragments or oligomer fragments, and

x is an integer between 1 and 1,000.

99. The suture of claim 98, wherein x is between 1 and 900.

100. The suture of claim 98, wherein a is between 1 and 1,400.

101. The suture of claim 98, wherein b is between 1 and 1,400.

102. The suture of claim 98, wherein m is between 2 and 900.

103. The suture of claim 98, wherein j is 0 or 1.

104. The suture of claim 98, wherein j is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

105. The suture of claim 98, wherein R' is an aryl or an aryl-containing group.

106. The suture of claim 105, wherein the aryl group is selected from naphthyl and phenyl, wherein the aryl-containing group comprises naphthyl or phenyl.

107. The suture of claim 98, wherein R ' is selected from the group consisting of 4,4' -diphenylmethane, 3' -dimethylphenyl, 3' -dimethyl-diphenylmethane, 4,6' -xylylene and p-phenylene.

108. The suture of claim 98, wherein R' is C ₂ -C ₁₂ Alkylene or C ₅ -C ₁₂ Cycloalkyl groups.

109. The suture of claim 98, wherein R 'is selected from the group consisting of 4,4' -dicyclohexylmethane, isophorone, lysine, cyclohexyl, 3, 5-trimethylcyclohexyl, and 2, 4-trimethylhexamethylene.

110. The suture of claim 98, wherein R' is a polymer segment or an oligomer segment.

111. The suture of claim 98, wherein j = 0.

112. The suture of claim 98, wherein R ₁ is-CH ₃ 。

113. The suture of claim 98, wherein R ₁ is-H.

114. The suture of claim 98, wherein R' is isophorone or lysine.

115. The suture of claim 98, wherein j = 0 and R ₁ is-H.

116. The suture of claim 98, wherein j = 0 and R ₁ is-CH ₃ 。

117. The suture of claim 98, wherein R' is a hexamethylene group, j = 4 and R ₁ is-H.

118. The suture of claim 86, wherein the polymer has formula (II):

Wherein the method comprises the steps of

Each r and k independently of the other is an integer between 1 and 2,000,

m is an integer between 2 and 1,000,

each j is independently an integer between 0 and 20,

z is an integer between 1 and 1,000.

119. The suture of claim 118, wherein z is between 1 and 900.

120. The suture of claim 118, wherein r is between 1 and 1,400.

121. The suture of claim 118, wherein k is between 1 and 1,400.

122. The suture of claim 118, wherein m is between 2 and 900.

123. The suture of claim 118, wherein j is 0.

124. The suture of claim 118, wherein j is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

125. The suture of claim 118, wherein R' is an aryl or an aryl-containing group.

126. The suture of claim 125, wherein the aryl is selected from the group consisting of naphthyl and phenyl; and wherein the aryl-containing group comprises a naphthyl or phenyl group.

127. The suture of claim 118, wherein R ' is selected from the group consisting of 4,4' -diphenylmethane, 3' -dimethylphenyl, 3' -dimethyl-diphenylmethane, 4,6' -xylylene and p-phenylene.

128. The suture of claim 118, wherein R' is C ₂ -C ₁₂ Alkylene or C ₅ -C ₁₂ Cycloalkyl groups.

129. The suture of claim 118, wherein R 'is selected from the group consisting of 4,4' -dicyclohexylmethane, cyclohexyl, 3, 5-trimethylcyclohexyl, and 2, 4-trimethylhexamethylene.

130. The suture of claim 118, wherein R' is a polymer fragment or an oligomer fragment.

131. The suture of claim 130, wherein the polymer or oligomer segments are selected from the group consisting of polypropylene oxide, polytetrahydrofuran, polyethylene oxide, copolymers of polyethylene oxide and polypropylene oxide, polydimethyl siloxane, polycaprolactone, oligopeptides, oligosaccharides, and combinations thereof.

132. The fiber of claim 130, wherein the polymer segment or oligomer segment is selected from the group consisting of polypropylene oxide-containing chains, polytetrahydrofuran-containing chains, polyethylene oxide-containing chains, copolymers of polyethylene oxide and polypropylene oxide, polydimethylsiloxane-containing chains, polycaprolactone-containing chains, oligopeptide-containing chains, oligosaccharide-containing chains, and combinations thereof.

133. The fiber of claim 130, wherein the polymer segment or oligomer segment is selected from the group consisting of polypropylene oxide-rich chains, polytetrahydrofuran-rich chains, polyethylene oxide-rich chains, copolymers of polyethylene oxide and polypropylene oxide, polydimethylsiloxane-rich chains, polycaprolactone-rich chains, oligopeptide-rich chains, oligosaccharide-rich chains, and combinations thereof.

134. The suture of claim 118, wherein R' "is a polymer segment or an oligomer segment.

135. The suture of claim 134, wherein the polymer or oligomer segments are selected from the group consisting of polypropylene oxide, polytetrahydrofuran, polyethylene oxide, copolymers of polyethylene oxide and polypropylene oxide, polydimethyl siloxane, polycaprolactone, oligopeptides, oligosaccharides, and combinations thereof.

136. The fiber of claim 134, wherein the polymer segment or oligomer segment is selected from the group consisting of polypropylene oxide-containing chains, polytetrahydrofuran-containing chains, polyethylene oxide-containing chains, copolymers of polyethylene oxide and polypropylene oxide, polydimethylsiloxane-containing chains, polycaprolactone-containing chains, oligopeptide-containing chains, oligosaccharide-containing chains, and combinations thereof.

137. The fiber of claim 134, wherein the polymer segment or oligomer segment is selected from the group consisting of polypropylene oxide-rich chains, polytetrahydrofuran-rich chains, polyethylene oxide-rich chains, copolymers of polyethylene oxide and polypropylene oxide, polydimethylsiloxane-rich chains, polycaprolactone-rich chains, oligopeptide-rich chains, oligosaccharide-rich chains, and combinations thereof.

138. The suture of claim 86, wherein the polymer has formula (III):

-{-T-CO-NH-R'-NH-CO-} _X formula (III)

Wherein the method comprises the steps of

p is an integer between 1 and 100,

each r and k independently of the other is an integer between 1 and 500,

m is an integer between 2 and 100,

Each j is independently an integer between 0 and 10,

R ₁ is H or C ₁ -C ₁₂ Alkyl group, and

x is an integer between 1 and 300.

139. The suture of claim 86, wherein the polymer has formula (IV):

HOOC-T-COOH formula (IV)

Wherein the method comprises the steps of

p is an integer between 1 and 100,

each r and k independently of the other is an integer between 1 and 500,

m is an integer between 2 and 100,

j are each independently an integer between 0 and 10, and

R ₁ is H or C ₁ -C ₁₂ An alkyl group.

140. The suture of claim 86, wherein the polymer has formula (V):

-{-T-CO-NH-R'-CO-NH-R'-NH-CO-R”'-CO-NH-R'-NH-CO-} _z (V)

Wherein the method comprises the steps of

x is an integer between 1 and 300,

p is an integer between 1 and 100,

each r and k independently of the other is an integer between 1 and 500,

m is an integer between 2 and 100,

j are each independently an integer between 0 and 10, and

R ₁ is H or C ₁ -C ₁₂ An alkyl group.

141. The suture of claim 86, wherein the ABA tri-block or AB di-block polymer is chain extended with or coupled with or crosslinked with a difunctional compound.

142. The suture of claim 141, wherein said difunctional compound is selected from diisocyanates.

143. The suture of claim 142, wherein said diisocyanate is Hexamethylene Diisocyanate (HDI).

144. The suture of claim 141, wherein chain extension or coupling is by an extender of formula (VI):

l' -OC-R "-CO-L type (VI)

Wherein the method comprises the steps of

145. The suture of claim 86, the polymer having a PO/CL ratio of between 0.05 and 100.

146. The suture of claim 145, the polymer having a PO/CL ratio of between 0.1 and 30.

147. The suture of claim 145, the polymer being a tri-block polymer having a PO/CL ratio of between 0.05 and 8.

148. The suture of claim 145, wherein the PO/CL ratio is between 0.1 and 5.

149. The suture of claim 86, wherein the polymer is a tri-block polymer having a molecular weight between 2,000da and 5000,000 da.

150. The suture of claim 149, wherein said tri-block polymer has a molecular weight between 2,000da and 200,000 da.

151. The suture of claim 149, wherein the tri-block polymer has a molecular weight of 165,320da, 86,660da, 82,660da, 62,280da, 60,440da, 47,330da, 43,330da, 40,760da, 39, 460 da, 32,640da, 30,220da, 23,732da, 23, 6615 da, 22,760da, 21,380da, 19, 730 da, 17, 460 da, 15,866da, 14,920da, 14, 850 da, 11,866da, 11,690da, 9,752da, 8,928da, 7,933da, 5,964da, 5,876da, or 3,938 da.

152. The suture of claim 98, wherein the tri-block is a polymer of formula (I) wherein x is between 2 and 300.

153. The suture of claim 98, the polymer being a tri-block polymer having between 10 and 2,000 caprolactone units.

154. The suture of claim 118, wherein the tri-block is a polymer of formula (II) wherein z is between 2 and 300.

155. The suture of claim 118, said polymer being a tri-block polymer having between 10 and 2,000 caprolactone units.

156. The suture of claim 153, wherein the number of caprolactone units is selected from 1380, 690, 520, 460, 345, 340, 276, 260, 230, 173, 170, 138, 130, 113, 104, 85, 69, 68, 52, 35, 34, 26, and 17.

157. The suture of claim 155, wherein the number of caprolactone units is selected from 1380, 690, 520, 460, 345, 340, 276, 260, 230, 173, 170, 138, 130, 113, 104, 85, 69, 68, 52, 35, 34, 26, and 17.

158. The suture of claim 153, wherein the number of PPO units in a tri-block polymer is 34, 52, 69 or 138.

159. The suture of claim 155, wherein the number of PPO units in a tri-block polymer is 34 or 52.

160. The suture of claim 155, wherein the number of PPO units in a tri-block polymer is 69 or 138.

161. The suture of claim 86, the polymer being any one of the following polymers numbered 1 to 28 tri-block polymers:

162. The suture of any one of claims 86-161, composed of the polymer.

163. The suture of any of claims 86-161 comprising a polymer selected from the group consisting of a polymer of formula (I) as defined in claim 98 or a polymer of formula (II) as defined in claim 118 or a polymer of formula (III) as defined in claim 138 or a polymer of formula (IV) as defined in claim 139 or a polymer of formula (V) as defined in claim 140 or a polymer numbered 1 to 28 as defined in claim 161.

164. The suture of any one of claims 86-161 for use in a surgical procedure of a human or non-human subject.

165. The suture of claim 164, for use in surgery.

166. The suture of any one of claims 86-161, in a form selected from the group consisting of a monofilament suture and a multifilament suture.

167. The suture of claim 166, being a monofilament suture made from a single strand of the polymer.

168. The suture of claim 166, being a multifilament suture made from a plurality of filaments, each filament comprising a polymer having the same or different composition.

169. The suture of any one of claims 86-161, coated with at least one coating material selected from the group consisting of an active material and an inactive material.

170. The suture of claim 169, wherein the active material is selected from bioactive agents.

171. The suture of claim 170, wherein the bioactive agent is selected from anticoagulants; a fibrinolytic material; steroidal and non-steroidal anti-inflammatory agents; calcium channel blockers; an antioxidant; an antibiotic; a prokinetic agent that promotes intestinal motility; an agent that prevents collagen cross-linking; an agent for preventing degranulation of mast cells.

172. The suture of claim 169, wherein the non-active material is selected from the group consisting of dyes, polymeric materials, thickeners, agents that affect hydrophilicity, agents that affect knottability, agents that affect surface mechanical properties, agents that exhibit mechanical cushioning to prevent tissue damage, and agents that affect lubricity.